U.S. patent number 5,610,303 [Application Number 08/411,838] was granted by the patent office on 1997-03-11 for arylamino pyrimidine compound.
This patent grant is currently assigned to Ube Industries, Ltd.. Invention is credited to Shigeharu Anpeiji, Hiroshi Fujiwara, Tomio Kimura, Yoshiaki Kuroki.
United States Patent |
5,610,303 |
Kimura , et al. |
March 11, 1997 |
**Please see images for:
( Certificate of Correction ) ** |
Arylamino pyrimidine compound
Abstract
A pyrimidine derivative represented by the formula (II) or
(III): ##STR1## (wherein R.sup.1 and R.sup.2 each represent H, a
halogen, amino, nitro, an unsubstituted or substituted alkyl, an
alkoxy or an alkoxycarbonyl, or R.sup.1 and R.sup.2 are bonded
together to form an unsubstituted or substituted alkylene; R.sup.3
represents an aralkyl or a hetero aromatic ring type-alkyl, R.sup.4
represents H or acyl, R.sup.5 represents H, OH or an alkoxy,
R.sup.6 represents H, a halogen, an alkyl or an alkoxy, X
represents --CH=, --CH=CH--(CH.sub.2).sub.p --, --CH.sub.2 -- or
--CH.sub.2 CH.sub.2 --(CH.sub.2).sub.p --, Y represents =CH--
(CH.sub.2).sub.p --, --CH.sub.2 --(CH.sub.2).sub.p --, a single
bond or a double bond, p represents 0 or 1, and . . . represents a
single bond or a double bond), and a salt thereof have selective
acetylcholinesterase-inhibiting activities and selective A type
monoamine oxidase-inhibiting activities, and are useful as an
antidepressant and an agent for curing senile dementia.
Inventors: |
Kimura; Tomio (Niiza,
JP), Kuroki; Yoshiaki (Ube, JP), Fujiwara;
Hiroshi (Ube, JP), Anpeiji; Shigeharu (Ube,
JP) |
Assignee: |
Ube Industries, Ltd. (Ube,
JP)
|
Family
ID: |
17429767 |
Appl.
No.: |
08/411,838 |
Filed: |
April 3, 1995 |
PCT
Filed: |
October 01, 1993 |
PCT No.: |
PCT/JP93/01412 |
371
Date: |
April 03, 1995 |
102(e)
Date: |
April 03, 1995 |
PCT
Pub. No.: |
WO94/07890 |
PCT
Pub. Date: |
April 14, 1994 |
Foreign Application Priority Data
|
|
|
|
|
Oct 5, 1992 [JP] |
|
|
4-266353 |
|
Current U.S.
Class: |
544/326; 544/253;
544/329; 544/298; 544/284 |
Current CPC
Class: |
C07D
405/14 (20130101); A61P 25/28 (20180101); C07D
401/14 (20130101); C07D 409/14 (20130101); C07D
401/12 (20130101); A61P 25/18 (20180101) |
Current International
Class: |
C07D
405/14 (20060101); C07D 405/00 (20060101); C07D
409/14 (20060101); C07D 409/00 (20060101); C07D
401/14 (20060101); C07D 401/12 (20060101); C07D
401/00 (20060101); C07D 401/10 () |
Field of
Search: |
;544/253,298,326,329,284 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0067630 |
|
May 1985 |
|
EP |
|
0378207 |
|
Jul 1990 |
|
EP |
|
57-203072 |
|
Dec 1982 |
|
JP |
|
3-173867 |
|
Jul 1991 |
|
JP |
|
Primary Examiner: Gupta; Yogendra N.
Attorney, Agent or Firm: Frishauf, Holtz, Goodman, Langer
& Chick, P.C.
Claims
We claim:
1. A pyrimidine compound of the formula (I): ##STR146## wherein
R.sup.1 and R.sup.2 each represent a hydrogen atom, a halogen atom,
an amino group, a nitro group, an alkyl group, a lower alkoxy group
or a lower alkoxycarbonyl group, or R.sup.1 and R.sup.2 are bonded
together to form a C.sub.3 -.sub.6 alkylene group, and said alkyl
group and alkylene group being unsubstituted or substituted by a
halogen, hydroxy, a lower alkoxy, a lower alkenyloxy, an aryloxy,
an aralkyloxy or an acyloxy.
R.sup.3 represents an aralkyl group or a C.sub.1 -C.sub.4 alkyl
group substituted by a hetero aromatic ring, the hetero aromatic
ring comprising a 5- or 6-membered aromatic heteromonocyclic group
having one or two hetero atoms selected from the group consisting
of nitrogen, oxygen and sulfur, or a fused aromatic group
comprising a benzene ring fused with said 5- or 6-membered aromatic
heteromonocyclic group, and the aryl portion of said aralkyl group
and said C.sub.1 -C.sub.4 alkyl group being unsubstituted or
substituted by a halogen, amino, alkanoylamino, cyano, nitro,
hydroxy, a lower alkyl, a lower alkoxy, an aralkyloxy, an
alkylenedioxy, a halogeno-lower alkyl or a halogeno-lower
alkoxy,
R.sup.4 represents a hydrogen atom or an acyl group,
R.sup.5 represents a hydrogen atom, a hydroxy group or a lower
alkoxy group,
A represents ##STR147## where R.sup.6 represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group,
X represents --CH=, --CH=CH--(CH.sub.2).sub.p --, --CH.sub.2 -- or
--CH.sub.2 CH.sub.2 --(CH.sub.2).sub.p --,
Y represents =CH--(CH.sub.2).sub.p --, --CH.sub.2
--(CH.sub.2).sub.p --, a single bond or a double bond and p
represents 0 or 1,
. . . represents a single bond or a double bond, and when . . .
represents a double bond or X represents --CH=, or Y represents a
double bond, R.sup.5 does not exist, and
a salt thereof.
2. The pyrimidine compound and a salt thereof according to claim 1
which is represented by the formula (II): ##STR148## wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, X and . . .
have the same meanings as defined above in claim 1.
3. The pyrimidine compound and a salt thereof according to claim 1
or 2, wherein R.sup.1 and R.sup.2 are bonded together to form a
C.sub.3-6 straight or branched alkylene group.
4. The pyrimidine compound and a salt thereof according to claim 3,
wherein the alkylene group formed by bonding R.sup.1 and R.sup.2
together is a trimethylene group or a tetramethylene group.
5. The pyrimidine compound and a salt thereof according to claim 1,
or 2, wherein R.sup.1 and R.sup.2 are the same or different and
each represent a hydrogen atom, a fluorine atom, a chlorine atom, a
bromine atom or a C.sub.1-7 straight or branched alkyl group.
6. The pyrimidine compound and a salt thereof according to claim 5,
wherein one of R.sup.1 and R.sup.2 is a C.sub.1-4 alkyl group and
the other is a hydrogen atom, a chlorine atom or a C.sub.1-4 alkyl
group.
7. The pyrimidine compound and a salt thereof according to claim 6,
wherein R.sup.1 is a C.sub.1-4 alkyl group and R.sup.2 is a
hydrogen atom or a C.sub.1-4 alkyl group.
8. The pyrimidine compound and a salt thereof according to claim 1
or 2, wherein R.sup.3 is a benzyl group, a sec-phenethyl group, a
fluorobenzyl group, a chlorobenzyl group, a methoxybenzyl group, a
cyanobenzyl group, a nitrobenzyl group, a 2-thienylmethyl group, a
2-furylmethyl group, a 2-pyridylmethyl group or a
6-methyl-2-pyridylmethyl group.
9. The pyrimidine compound and a salt thereof according to claim 8,
wherein R.sup.3 is a benzyl group.
10. The pyrimidine compound and a salt thereof according to claim 1
or 2, wherein R.sup.4 is a hydrogen atom or an acetyl group.
11. The pyrimidine compound and a salt thereof according to claim 1
or 2, wherein R.sup.5 is a hydrogen atom.
12. The pyrimidine compound and a salt thereof according to claim
2, wherein R.sup.6 is a hydrogen atom, a chlorine atom, a fluorine
atom or a methoxy group.
13. The pyrimidine compound and a salt thereof according to claim
2, wherein all of R.sup.4, R.sup.5 and R.sup.6 are hydrogen
atoms.
14. The pyrimidine compound and a salt thereof according to claim
2, wherein X is --CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH=CH--
and . . . is a single bond.
15. The pyrimidine compound and a salt thereof according to claim
2, which is selected from the group consisting of
(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]a
niline,
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-
4-yl)propenoyl]aniline,
N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propano
yl]aniline,
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-([1-(2-thienylmethyl)piperidin-4
-yl]acetyl)aniline,
N-(5-methylpyrimidin-4-yl)-4-{[1-(2-thienylmethyl)-piperidin-4-yl]acetyl}an
iline and
N-(5-ethylpyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline.
16. The pyrimidine compound and a salt thereof according to claim
2, wherein said compound is
N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]anil
ine.
17. The pyrimidine compound and a salt thereof according to claim
2, wherein said compound is
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-y
l)propanoyl]aniline.
18. The pyrimidine compound and a salt thereof according to claim
2, wherein said compound is
N-(5-methylpyrimidin-4-yl)-4[(1-benzylpiperidin-4-yl)acetyl]aniline.
19. The pyrimidine compound and a salt thereof according to claim
2, wherein said compound is
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)
acetyl]aniline.
20. The pyrimidine compound and a salt thereof according to claim
2, wherein said compound is
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-{3-[1-(2-pyridylmethyl)piperidi
n-4-yl]propanoyl}aniline.
21. The pyrimidine compound and a salt thereof according to claim
16, wherein
R.sup.1 and R.sup.2 each represent a hydrogen atom, a halogen atom,
an amino group, a nitro group, a C.sub.1 -C.sub.10 alkyl group, a
C.sub.1 -C.sub.4 alkoxy group or a C.sub.2 -C.sub.5 alkoxycarbonyl
group or R.sup.1 and R.sup.2 are bonded together to form a C.sub.3
-C.sub.6 alkylene group, and said C.sub.1 -C.sub.10 alkyl group and
said C.sub.3 -C.sub.6 alkylene group being unsubstituted or
substituted by a halogen, hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.3
-C.sub.4 alkenyloxy, phenoxy, naphthoxy, benzyloxy, phenethyloxy,
C.sub.7 -C.sub.8 aralkyloxy or C.sub.1 -C.sub.10 aliphatic
acyloxy,
R.sup.3 represents an aryl C.sub.1 -C.sub.4 alkyl group or a
C.sub.1 -C.sub.4 alkyl group substituted by a hetero aromatic ring,
the hetero aromatic ring comprising a 5- or 6-membered
hetermonocyclic group having one or two hetero atoms selected from
the group consisting of nitrogen, oxygen and sulfur, or a fused
aromatic group comprising a benzene ring fused with said 5- or
6-membered aromatic heteromonocyclic group, and the aryl portion of
said aryl C.sub.1 -C.sub.4 alkyl group and said C.sub.1 -C.sub.4
alkyl group which is substituted by said hetero aromatic ring being
unsubstituted or substituted by a halogen, amino, C.sub.1 -C.sub.4
alkanoylamino, cyano, nitro, hydroxy, C.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkoxy, benzyloxy, phenethyloxy, naphthylmethoxy,
C.sub.7 -C.sub.11 aralkyloxy, C.sub.1 -C.sub.2 alkylenedioxy, a
halogeno-C.sub.1 -C.sub.4 alkyl or a halogeno-C.sub.1 -C.sub.4
alkoxy,
R.sup.4 represents a hydrogen atom or a C.sub.1 -C.sub.10 aliphatic
acyl group,
R.sup.5 represents a hydrogen atom, a hydroxy group or a C.sub.1
-C.sub.4 alkoxy group, and
R.sup.6 represents a hydrogen atom, a halogen atom, a C.sub.1
-C.sub.4 alkyl group or a C.sub.1 -C.sub.4 alkoxy group.
Description
TECHNICAL FIELD
This invention relates to a pyrimidine derivative having both of an
excellent selective acetylcholinesterase-inhibiting activity and an
excellent selective A type monoamine oxidase-inhibiting activity
and useful as an antidepressant and an agent for curing senile
dementia, and a salt thereof.
BACKGROUND ART
In senile dementia, acetylcholine in a brain is lacking so that an
acetylcholinesterase-inhibiting agent has been studied. For
example, as an agent for curing dementia, there have been disclosed
1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, etc.
in Japanese Provisional Patent Publication No. 79151/1989 and
1-benzyl-4-[2-(4pyrrolidinobenzoyl)ethyl]piperidine, etc. in
Japanese Provisional Patent Publication No. 173867/1991 (U.S. Pat.
No. 5,177,087). However, senile dementia is generally accompanied
with symptoms such as depression, lowering of volition, etc. so
that various symptoms of senile dementia cannot be ameliorated
sufficiently only by an acetylcholinesterase-inhibiting agent. On
the other hand, depression is related to monoamine (noradrenaline,
serotonin), and as an antidepressant having an A type monoamine
oxidase-inhibiting activity, there has been known, for example,
4-(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta[d]pyrimidine as
disclosed in Japanese Provisional Patent Publication No.
203072/1982 (U.S. Pat. No. 4,450,162).
The present inventors have studied for many years in order to
develop a medicine having both of a selective
acetylcholinesterase-inhibiting activity and a selective A type
monoamine oxidase-inhibiting activity and therefore having a
further improved curing effect as an agent for curing senile
dementia, and consequently found that a pyrimidine derivative
having a specific structure with selective inhibiting activities to
both enzymes, to accomplish the present invention.
DISCLOSURE OF THE INVENTION
The present invention is a pyrimidine derivative represented by the
formula (I): ##STR2##
(wherein R.sup.1 and R.sup.2 each represent a hydrogen atom, a
halogen atom, an amino group, a nitro group, an alkyl group, a
lower alkoxy group or a lower alkoxycarbonyl group, or R.sup.1 and
R.sup.2 are bonded together to form an alkylene group, and said
alkyl group and alkylene group may be substituted by a halogen,
hydroxy, a lower alkoxy, a lower alkenyloxy, an aryloxy, an
aralkyloxy or an acyloxy.
R.sup.3 represents an aralkyl group or a hetero aromatic ring
type-alkyl group and the aryl portion of said aralkyl group and the
hetero aromatic ring portion of the hetero aromatic ring type-alkyl
group may be substituted by a halogen, amino, alkanoylamino, cyano,
nitro, hydroxy, a lower alkyl, a lower alkoxy, an aralkyloxy, an
alkylenedioxy, a halogeno-lower alkyl or a halogeno-lower
alkoxy.
R.sup.4 represents a hydrogen atom or an acyl group.
R.sup.5 represents a hydrogen atom, a hydroxy group or a lower
alkoxy group.
A represents ##STR3## where R.sup.6 represents a hydrogen atom, a
halogen atom, a lower alkyl group or a lower alkoxy group, X
represents --CH=, --CH=CH--(CH.sub.2).sub.p --, --CH.sub.2 -- or
--CH.sub.2 CH.sub.2 --(CH.sub.2).sub.p --, Y represents
=CH--(CH.sub.2).sub.p --, --CH.sub.2 --(CH.sub.2).sub.p --, a
single bond or a double bond and p represents 0 or 1.
Also, . . . represents a single bond or a double bond, and when . .
. represents a double bond or X represents --CH=, or Y represents a
double bond, R.sup.5 does not exist) and a salt thereof.
The compounds represented by the above formula (I) are roughly
classified into compounds represented by the following formula (II)
and formula (III): ##STR4##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, X, Y
and . . . have the same meanings as defined above)
As the halogen atom of R.sup.1 and R.sup.2, there may be mentioned
fluorine, chlorine, bromine and iodine; as the alkyl group, there
may be mentioned a C.sub.1-10 straight or branched alkyl group such
as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl; as the
lower alkoxy group, there may be mentioned a C.sub.1-4 straight or
branched lower alkoxy group such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy; as the
lower alkoxycarbonyl group, there may be mentioned a C.sub.2-5
atkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl; and as
the alkylene group formed by bonding R.sup.1 and R.sup.2 together,
there may be mentioned a C.sub.3-6 straight or branched alkylene
group such as trimethylene, 1-, 2- or 3-methyltrimethylene,
1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene,
1,3-dimethyltrimethylene, tetramethylene, 1- or
2-methyltetramethylene and 1,2-dimethyltetramethylene.
The above alkyl group and alkylene group may have a substituent(s).
As said substituent, there may be mentioned a halogen atom such as
fluorine, chlorine, bromine and iodine; a hydroxy group; a
C.sub.1-4 straight or branched lower alkoxy group such as methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and
t-butoxy; a C.sub.3-4 lower alkenyloxy group such as allyloxy and
2-butenyloxy; an aryloxy group such as phenoxy and naphthoxy; an
aralkyloxy group such as benzyloxy and phenethyloxy; a C.sub.1-10
aliphatic acyloxy group such as formyloxy, acetyloxy, propionyloxy,
butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy,
hexanoyloxy, heptanoyloxy, octanoyloxy, nonanonyloxy and
decanoyloxy; an aromatic aliphatic acyloxy group such as
phenylacetoxy and cinnamoyloxy; and an aromatic acyloxy group such
as benzoyloxy and naphthoyloxy.
As the groups of R.sup.1 and R.sup.2, preferred are a hydrogen
atom, a fluorine atom, a chlorine atom, a bromine atom, a C.sub.1-7
straight or branched alkyl group, a trimethylene group, a
tetramethylene group and a 2,2-dimethyltrimethylene group, and as
the group having a substituent(s), preferred are a hydroxymethyl
group, a fluoromethyl group, a chloromethyl group, a bromomethyl
group, a methoxymethyl group, a phenoxymethyl group, a
benzyloxymethyl group, an acetoxymethyl group, a propionyloxymethyl
group, a benzoyloxymethyl group, a 1- or 2-hydroxyethyl group, a 1-
or 2-fluoroethyl group, a 1- or 3-hydroxytrimethylene group, a 1-
or 3-fluorotrimethylene group, a 1- or 3-chlorotrimethylene group,
a 1- or 3-bromotrimethylene group, a 1- or 3-methoxytrimethylene
group, a 1- or 3-phenoxytrimethylene group, a 1- or
3-acetoxytrimethylene group, a 1,3-dihydroxytrimethylene group and
a 1,3-difluorotrimethylene group. As the groups of R.sup.1 and
R.sup.2, particularly preferred are a hydrogen atom, a fluorine
atom, a chlorine atom, a bromine atom, a methyl group, an ethyl
group, a propyl group, an isopropyl group, a butyl group, a
trimethylene group, a tetramethylene group and a
2,2-dimethyltrimethylene group, and as the group having a
substituent(s), particularly preferred are a hydroxymethyl group, a
fluoromethyl group, a methoxymethyl group, an acetoxymethyl group,
a 1- or 3-hydroxytrimethylene group, a 1- or 3-fluorotrimethylene
group, a 1- or 3-methoxytrimethylene group, a 1- or
3-acetoxytrimethylene group and a 1,3-difluorotrimethylene group.
It is particularly preferred that R.sup.1 and R.sup.2 form a
trimethylene group or a tetramethylene group in combination, or one
is a C.sub.1-4 alkyl group and the other is a hydrogen atom, a
chlorine atom or a C.sub.1-4 alkyl group, and most preferred is a
compound wherein R.sup.1 and R.sup.2 form a trimethylene group in
combination or R.sup.1 is a C.sub.1-4 alkyl group and R.sup.2 is a
hydrogen atom or a C.sub.1-4 alkyl group.
As the aralkyl group of R.sup.3, there may be mentioned an aryl
C.sub.1-4 alkyl group such as benzyl, phenethyl, sec-phenethyl,
phenylpropyl, phenylbutyl, naphthylmethyl and diphenylmethyl; and
as the hetero aromatic ring type-alkyl group, there may be
mentioned a hetero aromatic ring type-C.sub.1-4 alkyl group such as
thienylmethyl, thienylethyl, thienylpropyl, thienylbutyl,
furylmethyl, pyridylmethyl, pyrimidinylmethyl, thiazolylmethyl,
oxazolylmethyl, imidazolylmethyl, 2-benzothiazolylmethyl,
2-benzoxazolylmethyl and 2-benzoimidazolylmethyl. The aryl portion
of the above aralkyl group and the hetero aromatic ring portion of
the hetero aromatic ring type-alkyl group may have a
substituent(s), and as said substituent, there may be mentioned a
halogen atom such as fluorine, chlorine, bromine and iodine; a
C.sub.1-4 straight or branched lower alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl; a
C.sub.1-4 straight or branched lower alkoxy group such as methoxy,
ethoxy, propoxy, iso-propoxy, butoxy, isobutoxy, sec-butoxy and
t-butoxy; an aralkyloxy group such as benzyloxy, phenethyloxy and
naphthylmethoxy; an alkylenedioxy group such as methylenedioxy and
ethylenedioxy; an amino group, a C.sub.1-4 alkanoylamino such as
formylamino, acetylamino, propionylamino, butyrylamino and
isobutyrylamino; a nitro group; a cyano group; a hydroxy group; a
C.sub.1-4 halogeno-lower alkyl group such as fluoromethyl,
chloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,
2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl
and 4-fluorobutyl; and a C.sub.1-4 halogeno-lower alkoxy group such
as fluoromethoxy, difluoromethoxy, trifluoromethoxy,
2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy,
2,2,2-trifluoroethoxy, 3-fluoropropoxy and 4-fluorobutoxy.
As the group of R.sup.3, preferred are a benzyl group, a
sec-phenethyl group, a fluorobenzyl group, a methoxybenzyl group,
an ethylenedioxybenzyl group, a hydroxybenzyl group, a chlorobenzyl
group, a methylbenzyl group, a trifluoromethylbenzyl group, an
aminobenzyl group, an acetylaminobenzyl group, a nitrobenzyl group,
a cyanobenzyl group, a diphenylmethyl group, a
di(4-fluorophenyl)methyl group, a thienylmethyl group, a
furylmethyl group, a pyridylmethyl group, a methylpyridylmethyl
group and a pyrimidinylmethyl group. As the group of R.sup.3,
particularly preferred are a benzyl group, a sec-phenethyl group, a
2-, 3- or 4-fluorobenzyl group, a 2-, 3- or 4-chlorobenzyl group, a
2-, 3- or 4-methoxybenzyl group, a 2-, 3- or 4-cyanobenzyl group, a
2-, 3- or 4-nitrobenzyl group, a 2-thienylmethyl group, a
2-furylmethyl group, a 2-pyridylmethyl group and a
6-methyl-2-pyridylmethyl group.
As the acyl group of R.sup.4, there may be mentioned a C.sub.1-10
aliphatic acyl group such as formyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,
octanoyl, nonanoyl and decanoyl; an aromatic aliphatic acyl group
such as phenylacetyl and cinnamoyl; and an aromatic acyl group such
as benzoyl and naphthoyl.
As the group of R.sup.4, preferred are a hydrogen atom, a formyl
group, an acetyl group, a propionyl group, a butyryl group and a
pivaloyl group, and particularly preferred are a hydrogen atom and
an acetyl group.
As the lower alkoxy group of R.sup.5, the same lower alkoxy group
mentioned in R.sup.1 and R.sup.2 may be mentioned.
As the group of R.sup.5, preferred are a hydrogen atom, a hydroxy
group, a methoxy group and an ethoxy group, and particularly
preferred is a hydrogen atom.
As the halogen atom and the lower alkoxy group of R.sup.6, the same
halogen atom and lower alkoxy group mentioned in R.sup.1 and
R.sup.2 may be mentioned; and as the lower alkyl group, there may
be mentioned a C.sub.1-4 straight or branched alkyl group such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl and
sec-butyl.
As the group of R.sup.6, preferred are a hydrogen atom, a fluorine
atom, a chlorine atom, a methyl group and a methoxy group, and
particularly preferred are a hydrogen atom, a fluorine atom, a
chlorine atom and a methoxy group.
As X in the formula (II), --CH=, --CH.sub.2 --, --CH.sub.2 CH.sub.2
-- and --CH=CH-- are particularly preferred. As Y in the formula
(III), --CH.sub.2 -- and =CH-- are particularly preferred. The
compound of the formula (II) is preferred for achieving the object
of the present invention.
The . . . is preferably a single bond.
The compounds of the formula (I), the formula (II) and the formula
(III) may be converted into salts, if necessary. As a
pharmaceutically acceptable salt, there may be mentioned a salt of
a mineral acid such as hydrochloride, hydrobromide, hydroiodide,
sulfate and phosphate; a sulfonate such as methanesulfonate,
ethanesulfonate, benzenesulfonate and p-toluenesulfonate; oxalate,
maleate, fumarate and tartrate; and an acid addition salt of an
organic acid such as citrate. The compounds of the formula (I), the
formula (II) and the formula (III) or salts thereof may exist as
hydrates.
Examples of the compound of the formula (II) are shown in Table 1
(Compound II), and examples of the compound of the formula (III)
are shown in Table 2 (Compound III), respectively.
TABLE 1
__________________________________________________________________________
(Compound II) ##STR5## ##STR6## ##STR7## ##STR8## ##STR9##
##STR10## ##STR11## ##STR12##
__________________________________________________________________________
1 CH.sub.2 CH.sub.2 CH.sub.2 H H CH.sub.2 ##STR13## benzyl 2 " " "
(CH.sub.2).sub.2 " " 3 " " " (CH.sub.2).sub.3 " " 4 " " " CH
##STR14## " 5 " " " CHCH ##STR15## " 6 " " " CHCHCH.sub.2 " " 7 " "
" CH.sub.2 " 4-fluoro- benzyl 8 " " " (CH.sub.2).sub.2 " 4-fluoro-
benzyl 9 " " " (CH.sub.2).sub.3 " 4-fluoro- benzyl 10 " " " CH
##STR16## 4-fluoro- benzyl 11 " " " CHCH ##STR17## 4-fluoro- benzyl
12 " " " CHCHCH.sub.2 " 4-fluoro- benzyl 13 " " " CH.sub.2 "
3-fluoro- benzyl 14 " " " (CH.sub.2).sub.2 " 3-fluoro- benzyl 15 "
" " (CH.sub.2).sub.3 " 3-fluoro- benzyl 16 " " " CH ##STR18##
3-fluoro- benzyl 17 " " " CHCH ##STR19## 3-fluoro- benzyl 18 " " "
CHCHCH.sub.2 " 3-fluoro- benzyl 19 CH.sub.2 CH.sub.2 CH.sub.2 H H
CH.sub.2 ##STR20## 2-fluoro- benzyl 20 " " " (CH.sub.2).sub.2 "
2-fluoro- benzyl 21 " " " (CH.sub.2).sub.3 " 2-fluoro- benzyl 22 "
" " CH ##STR21## 2-fluoro- benzyl 23 " " " CHCH ##STR22## 2-fluoro-
benzyl 24 " " " CHCHCH.sub.2 " 2-fluoro- benzyl 25 " " " CH.sub.2 "
4-meth- oxy- benzyl 26 " " " (CH.sub.2).sub.2 " 4-meth- oxy- benzyl
27 " " " (CH.sub.2).sub.3 " 4-meth- oxy- benzyl 28 " " " CH
##STR23## 4-meth- oxy- benzyl 29 " " " CHCH ##STR24## 4-meth- oxy-
benzyl 30 " " " CHCHCH.sub.2 " 4-meth- oxy- benzyl 31 " " "
CH.sub.2 " 3-meth- oxy- benzyl 32 " " " (CH.sub.2).sub.2 " 3-meth-
oxy- benzyl 33 " " " (CH.sub.2).sub.3 " 3-meth- oxy- benzyl 34 " "
" CH ##STR25## 3-meth- oxy- benzyl 35 " " " CHCH ##STR26## 3-meth-
oxy- benzyl 36 " " " CHCHCH.sub.2 " 3-meth- oxy- benzyl 37 " " "
CH.sub.2 " 2-meth- oxy- benzyl 38 CH.sub.2 CH.sub.2 CH.sub.2 H H
(CH.sub.2).sub.2 ##STR27## 2-meth- oxy- benzyl 39 " " "
(CH.sub.2).sub.3 " 2-meth- oxy- benzyl 40 " " " CH ##STR28##
2-meth- oxy- benzyl 41 " " " CHCH ##STR29## 2-meth- oxy- benzyl 42
" " " CHCHCH.sub.2 " 2-meth- oxy- benzyl 43 " " " CH.sub.2 " 4-
hydroxy- benzyl 44 " " " (CH.sub.2).sub.2 " 4- hydroxy- benzyl 45 "
" " (CH.sub.2).sub.3 " 4- hydroxy- benzyl 46 " " " CH ##STR30## 4-
hydroxy- benzyl 47 " " " CHCH ##STR31## 4- hydroxy- benzyl 48 " " "
CHCHCH.sub.2 " 4- hydroxy- benzyl 49 " " " CH.sub.2 " 4-chloro-
benzyl 50 " " " (CH.sub.2).sub.2 " 4-chloro- benzyl 51 " " "
(CH.sub.2).sub.3 " 4-chloro- benzyl 52 " " " CH ##STR32## 4-chloro-
benzyl 53 " " " CHCH ##STR33## 4-chloro- benzyl 54 " " "
CHCHCH.sub.2 " 4-chloro- benzyl 55 " " " CH.sub.2 " 3-chloro-
benzyl 56 " " " (CH.sub.2).sub.2 " 3-chloro- benzyl 57 CH.sub.2
CH.sub.2 CH.sub.2 H H (CH.sub.2).sub.3 ##STR34## 3-chloro- benzyl
58 " " " CH ##STR35## 3-chloro- benzyl 59 " " " CHCH ##STR36##
3-chloro- benzyl 60 " " " CHCHCH.sub.2 " 3-chloro- benzyl 61 " " "
CH.sub.2 " 2-chloro- benzyl
62 " " " (CH.sub.2).sub.2 " 2-chloro- benzyl 63 " " "
(CH.sub.2).sub.3 " 2-chloro- benzyl 64 " " " CH ##STR37## 2-chloro-
benzyl 65 " " " CHCH ##STR38## 2-chloro- benzyl 66 " " "
CHCHCH.sub.2 " 2-chloro- benzyl 67 " " " CH.sub.2 " 4-methyl-
benzyl 68 " " " (CH.sub.2).sub.2 " 4-methyl- benzyl 69 " " "
(CH.sub.2).sub.3 " 4-methyl- benzyl 70 " " " CH ##STR39## 4-methyl-
benzyl 71 " " " CHCH ##STR40## 4-methyl- benzyl 72 " " "
CHCHCH.sub.2 " 4-methyl- benzyl 73 " " " CH.sub.2 " 4-nitro- benzyl
74 " " " (CH.sub.2).sub.2 " 4-nitro- benzyl 75 " " "
(CH.sub.2).sub.3 " 4-nitro- benzyl 76 CH.sub.2 CH.sub.2 CH.sub.2 H
H CH ##STR41## 4-nitro- benzyl 77 " " " CHCH ##STR42## 4-nitro-
benzyl 78 " " " CHCHCH.sub.2 " 4-nitro- benzyl 79 " " " CH.sub.2 "
4-tri- fluoro- methyl- benzyl 80 " " " (CH.sub.2).sub.2 " 4-tri-
fluoro- methyl- benzyl 81 " " " CH ##STR43## 4-tri- fluoro- methyl-
benzyl 82 " " " (CH.sub.2).sub.3 ##STR44## 4-tri- fluoro- methyl-
benzyl 83 " " " CHCH " 4-tri- fluoro- methyl- benzyl 84 " " "
CHCHCH.sub.2 " 4-tri- fluoro- methyl- benzyl 85 " " " CH.sub.2 "
sec-phen- ethyl 86 " " " (CH.sub.2).sub.2 " sec-phen- ethyl 87 " "
" (CH.sub.2).sub.3 " sec-phen- ethyl 88 " " " CH ##STR45##
sec-phen- ethyl 89 " " " CHCH ##STR46## sec-phen- ethyl 90 " " "
CHCHCH.sub.2 " sec-phen- ethyl 91 " " " CH.sub.2 " diphenyl- methyl
92 " " " (CH.sub.2).sub.2 " diphenyl- methyl 93 " " "
(CH.sub.2).sub.3 " diphenyl- methyl 94 " " " CH ##STR47## diphenyl-
methyl 95 CH.sub.2 CH.sub.2 CH.sub.2 H H CHCH ##STR48## diphenyl-
methyl 96 " " " CHCHCH.sub.2 " diphenyl- methyl 97 " " " CH.sub.2 "
di(4- fluoro- phenyl)- methyl 98 " " " (CH.sub.2).sub.2 " di(4-
fluoro- phenyl)- methyl 99 " " " (CH.sub.2).sub.3 " di(4- fluoro-
phenyl)- methyl 100 " " " CH ##STR49## di(4- fluoro- phenyl)-
methyl 101 " " " CHCH ##STR50## di(4- fluoro- phenyl)- methyl 102 "
" " CHCHCH.sub.2 " di(4- fluoro- phenyl)- methyl 103 " " " CH.sub.2
" 2-thienyl- methyl 104 " " " (CH.sub.2).sub.2 " 2-thienyl- methyl
105 " " " (CH.sub.2).sub.3 " 2-thienyl- methyl 106 " " " CH
##STR51## 2-thienyl- methyl 107 " " " CHCH ##STR52## 2-thienyl-
methyl 108 " " " CHCHCH.sub.2 " 2-thienyl- methyl 109 " " "
CH.sub.2 " 2- pyridyl- methyl 110 " " " (CH.sub.2).sub.2 " 2-
pyridyl- methyl 111 " " " (CH.sub.2).sub.2 " 2- pyridyl- methyl 112
" " " CH ##STR53## 2- pyridyl- methyl 113 CH.sub.2 CH.sub.2
CH.sub.2 H H CHCH ##STR54## 2- pyridyl- methyl 114 " " "
CHCHCH.sub.2 " 2- pyridyl- methyl 115 " " " CH.sub.2 " 4- pyridyl-
methyl 116 " " " (CH.sub.2).sub.2 " 4- pyridyl- methyl 117 " " "
(CH.sub.2).sub.3 " 4- pyridyl- methyl 118 " " " CH ##STR55## 4-
pyridyl- methyl 119 " " " CHCH ##STR56## 4- pyridyl- methyl 120
" " " CHCHCH.sub.2 " 4- pyridyl- methyl 121 " " " CH.sub.2 " 2-pyr-
imidinyl- methyl 122 " " " (CH.sub.2).sub.2 " 2-pyr- imidinyl-
methyl 123 " " " (CH.sub.2).sub.3 " 2-pyr- imidinyl- methyl 124 " "
" CH ##STR57## 2-pyr- imidinyl- methyl 125 " " " CHCH ##STR58##
2-pyr- imidinyl- methyl 126 " " " CHCHCH.sub.2 " 2-pyr- imidinyl-
methyl 127 " " " CH.sub.2 " 4-pyr- imidinyl- methyl 128 " " "
(CH.sub.2).sub.2 " 4-pyr- imidinyl- methyl 129 " " "
(CH.sub.2).sub.3 " 4-pyr- imidinyl- methyl 130 " " " CH ##STR59##
4-pyr- imidinyl- methyl 131 " " " CHCH ##STR60## 4-pyr- imidinyl-
methyl 132 CH.sub.2 CH.sub.2 CH.sub.2 H H CHCHCH.sub.2 ##STR61##
4-pyr- imidinyl- methyl 133 " " " (CH.sub.2).sub.2 " 4-di- fluoro-
methoxy- benzyl 134 " " " " " 3-di- fluoro- methoxy- benzyl 135 " "
" " " 2-di- fluoro- methoxy- benzyl 136 H H " " (CH.sub.2).sub.2 "
benzyl 137 " CH.sub.3 " " " " " 138 " C.sub.2 H.sub.5 " " " " " 139
" C.sub.3 H.sub.7 " " " " " 140 " i-C.sub.3 H.sub.7 " " " " " 141 "
C.sub.4 H.sub.9 " " " " " 142 " sec-C.sub.4 H.sub.9 " " " " " 143 "
C.sub.6 H.sub.13 " " " " " 144 " C.sub.8 H.sub.17 " " " " " 145 "
C.sub.10 H.sub.21 " " " " " 146 " Cl " " " " " 147 " Br " " " " "
148 " OCH.sub.3 " " " " " 149 " OC.sub.2 H.sub.5 " " " " " 150
CH.sub.3 CH.sub.3 H H (CH.sub.2).sub.2 ##STR62## benzyl 151 C.sub.2
H.sub.5 " " " " " " 152 C.sub.3 H.sub.7 " " " " " " 153 i-C.sub.3
H.sub.7 " " " " " " 154 C.sub.4 H.sub.9 " " " " " " 155 sec-C.sub.4
H.sub.9 " " " " " " 156 i-C.sub.4 H.sub.9 " " " " " " 157 C.sub.5
H.sub.11 " " " " " " 158 C.sub.7 H.sub.15 " " " " " " 159 C.sub.9
H.sub.19 " " " " " " 160 Cl " " " " " " 161 Br " " " " " " 162 Cl "
" " CHCH " " 163 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " "
(CH.sub.2).sub.2 " " 164 CH(CH.sub.3)CH.sub.2 CH.sub.2 " " " " "
165 CH.sub.2 CH(CH.sub.3)CH.sub.2 " " " " " 166 CH.sub.2 CH.sub.2
CH(CH.sub.3) " " " " " 167 CH.sub.2 CH.sub.2 CH(OH) " " " " " 168
CH.sub.2 CH.sub.2 CH(OCH.sub.3) " " " " " 169 CH.sub.2 CH.sub.2
CH(OC.sub.2 H.sub.5) H H (CH.sub.2).sub.2 ##STR63## benzyl 170
CH.sub.2 CH.sub.2 CH(OC.sub.3 H.sub.7) " " " " " 171 CH.sub.2
CH.sub.2 CH(OCH.sub.2 CHCH.sub.2) " " " " " 172 CH.sub.2 CH.sub.2
CH(OCH.sub.2 C.sub.6 H.sub.5) " " " " " 173 CH.sub.2 CH.sub.2
CH(OCH.sub.3) " " CHCH " " 174 CH.sub.2 CH.sub.2 CH(OCOH) " "
(CH.sub.2).sub.2 " " 175 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " "
CHCH " " 176 CH.sub.2 CH.sub.2 CH(OCOCH.sub.3) " " (CH.sub.2).sub.2
" " 177 CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5) " " " " " 178
CH.sub.2 CH.sub.2 CH(OCOC.sub.3 H.sub.7) " " " " " 179 CH.sub.2
CH.sub.2 CH(OCOC.sub.5 H.sub.11) " " " " " 180 CH.sub.2 CH.sub.2
CH(OCOC.sub.9 H.sub.19) " " " " " 181 CH.sub.2 CH.sub.2
CH(OCOCH.sub.2 C.sub.6 H.sub.5) " " " " " 182 CH.sub.2 CH.sub.2
CH(OCOC.sub.6 H.sub.5) " " " " " 183 CH.sub.2 CH.sub.2 CH(F) " " "
" " 184 CH.sub.2 CH.sub.2 CH(Cl) " " " " " 185 CH.sub.2 CH.sub.2
CH(Br) " " " " " 186 CH.sub.2 CH.sub.2 C(F).sub.2 " " " " " 187
CH(Br)CH.sub.2 CH(Br) " " " " " 188 CH.sub.2 CH.sub.2 CH(F) H H
CHCH ##STR64## benzyl 189 CH.sub.3 H " " (CH.sub.2).sub.2 " " 190 "
Cl " " " " " 191 " Br " " " " " 192 " CH.sub.2 OH " " " " " 193 "
CH.sub.2 OCH.sub.3 " " " " " 194 " CH.sub.2 OCOCH.sub.3 " " " " "
195
" CH.sub.2 F " " " " " 196 " CH.sub.2 Cl " " " " " 197 C.sub.2
H.sub.5 H " " " " 2-pyr- imidinyl- methyl 198 CH.sub.2
C(CH.sub.3).sub.2 CH.sub.2 " " " " benzyl 199 CH.sub.3 CH.sub.3 " "
CHCH " " 200 C.sub.2 H.sub.5 C.sub.2 H.sub.5 " " " " " 201 CH.sub.2
C(CH.sub.3).sub.2 CH.sub.2 " " " " " 202 CH.sub.3 H " " " " " 203
C.sub.2 H.sub.5 " " " " " " 204 C.sub.3 H.sub.7 " " " " " " 205
C.sub.2 H.sub.5 " " " (CH.sub.2).sub.2 " " 206 C.sub.3 H.sub.7 " "
" " " " 207 CH.sub.2 CH.sub.2 CH(OC.sub.6 H.sub.5) H H
(CH.sub.2).sub.2 ##STR65## benzyl 208 CH.sub.2 CH.sub.2
CH(O-1-C.sub.10 H.sub.7 ) " " " " " 209 CH.sub.2 CH.sub.2 CH.sub.2
" " CHCH " 3- pyridyl- methyl 210 " " " (CH.sub.2).sub.2 " 3-
pyridyl- methyl 211 " " " CHCH " 2-methyl- benzyl 212 " " "
(CH.sub.2).sub.2 " 2-methyl- benzyl 213 " " " CHCH " 3-methyl-
benzyl 214 " " " (CH.sub.2).sub.2 " 3-methyl- benzyl 215 " " "
CH.sub.2 ##STR66## benzyl 216 " " " " ##STR67## " 217 " " " "
##STR68## " 218 " " " (CH.sub.2).sub.2 ##STR69## 4-cyano- benzyl
219 CH.sub.3 H " " CH.sub.2 " 2- pyridyl- methyl 220 " " " " " "
benzyl 221 CH.sub.2 CH.sub.2 CH.sub.2 COCH.sub.3 " (CH.sub.2).sub.2
" " 222 COOC.sub.2 H.sub.5 H H " " " " 223 C.sub.2 H.sub.5 C.sub.2
H.sub.5 " " " " "
224 CH.sub.2 CH.sub.2 CH.sub.2 " " " " 1- naphthyl- methyl 225 " "
" " " 3-cyano- benzyl 226 CH.sub.3 H H 2-F CH.sub.2 ##STR70##
benzyl 227 " " " 3-F " " " 228 " " " 3-Cl " " " 229 Cl " " H
(CH.sub.2).sub.2 " " 230 Br " " " " " " 231 CH.sub.2 CH.sub.2
CH.sub.2 " " " " 3,4- methyl- ene- dioxy- benzyl 232 " " " " "
3-tri- fluoro- methyl- benzyl 233 " " " " " 2,3-di- methoxy- benzyl
234 CH.sub.3 CH.sub.3 " " CH.sub.2 " benzyl 235 CH.sub.2 CH.sub.2
CH.sub.2 " " (CH.sub.2).sub.2 " 3,4- ethylene- dioxy- benzyl 236
CH.sub.2 CH.sub.2 CH(OH) " " CH.sub.2 " benzyl 237 CH.sub.2
CH.sub.2 CH(OCOCH.sub.3) " " " " " 238 CH.sub.2 CH.sub.2 CH.sub.2 "
" (CH.sub.2).sub.2 " 6- methyl-2- pyridyl- methyl 239 " " " " "
3-benzyl- oxy- benzyl 240 NO.sub.2 OCH.sub.3 " " " " benzyl 241
NH.sub.2 Cl " " " " " 242 CH.sub.2 CH.sub.2 CH.sub.2 H H
(CH.sub.2).sub.2 ##STR71## 2-nitro- benzyl 243 " " " " " 3-nitro-
benzyl 244 " " " " " 3-amino- benzyl 245 " " 2-OCH.sub.3 CH.sub.2 "
benzyl 246 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " " " " " 247
CH.sub.2 CH.sub.2 CH.sub.2 " 2-Cl " " " 248 CH.sub.3 H " H
(CH.sub.2).sub.2 " 2- pyridyl- methyl 249 CH.sub.2 CH.sub.2
CH.sub.2 " " " " 2-acetyl- amino- benzyl 250 CH.sub.3 H "
2-CH.sub.3 CH.sub.2 " benzyl 251 " " " 3-CH.sub.3 " " " 252 C.sub.2
H.sub.5 " " H " " " 253 C.sub.3 H.sub.7 " " " " " " 254 i-C.sub.3
H.sub.7 " " " " " " 255 C.sub.4 H.sub.9 " " " " " " 256 sec-C.sub.4
H.sub.9 " " " " " " 257 i-C.sub.4 H.sub.9 " " " " " " 258 CH.sub.3
" " " " " 2-thienyl- methyl 259 " " " " " " 3-thienyl- methyl 260 "
" " " " " 2-furyl- methyl 261 CH.sub.3 H H H CH.sub.2 ##STR72##
3-furyl- methyl 262 " " " " " " 3- pyridyl- methyl 263 " " " " " "
4- pyridyl- methyl 264 " " " " " " 2- pyr- imidinyl- methyl 265 " "
" " " " 4-pyr- imidinyl- methyl 266 " " " 3-OCH.sub.2 " " benzyl
267 CH.sub.2 CH.sub.2 CH.sub.2 " H " " 3-thienyl- methyl 268 " " "
" " 3- pyridyl- methyl 269 " " " " " 2-furyl- methyl 270 " " " " "
3-furyl- methyl 271 " " " (CH.sub.2).sub.2 " 4-amino- benzyl 272 "
" " " " 2-amino- benzyl 273 " " " " " 4-acetyl- amino- benzyl 274 "
" " " " 3-acetyl- amino- benzyl 275 CH.sub.3 H COH " CH.sub.2 "
benzyl 276 " " COC.sub.2 H.sub.5 " " " " 277 " " COC.sub.3 H.sub.7
" " " " 278 CH.sub.3 H COC.sub.4 H.sub.9 H CH.sub.2 ##STR73##
benzyl 279 " " COC.sub.6 H.sub.13 " " " " 280 " " COC.sub.8
H.sub.27 " " " " 281 " " COC.sub.10 H.sub.21 " " " " 282 " " H " "
##STR74## " 283 " " " " " ##STR75## " 284 " " " " " ##STR76## " 285
" " " 3-Br " ##STR77## " 286 " " " 3-C.sub.2 H.sub.5 " " " 287 " "
" 3-C.sub.3 H.sub.7 " " " 288 " " " 3-OC.sub.2 H.sub.5 " " " 289 "
" " 3-OC.sub.3 H.sub.7 " " " 290 " " " 3-OC.sub.4 H.sub.9 " " " 291
" " " H " " 4-ethoxy- benzyl 292 " " " " " " 4-butoxy- benzyl 293 "
" " " " " 4-t-butyl- benzyl 294 " " " " " " 4-di- fluoro- methyl-
benzyl 295 CH.sub.3 H H H CH.sub.2 ##STR78## 4-(2- fluoro- ethoxy)-
benzyl
296 " " " " " " 4- butyryl- amino- benzyl 297 H OC.sub.3 H.sub.7 "
" " " benzyl 298 " OC.sub.4 H.sub.9 " " " " " 299 CH.sub.2 CH.sub.2
CH.sub.2 CH(CH.sub.3) " " " " " 300 CH.sub.2 CH.sub.2 CH(OCH.sub.2
CH.sub.2 C.sub.6 H.sub.5) " " " " " 301 CH.sub.3 H " " " " phen-
ethyl 302 " " " " " " diphenyl- methyl 303 C.sub.2 H.sub.5 " "
3-OCH.sub.3 " " benzyl 304 " " " 3-F " " " 305 " " " 3-Cl " " " 306
" " " 3-CH.sub.3 " " " 307 " " " H " " 2-thienyl- methyl 308
C.sub.3 H.sub.7 " " 3-OCH.sub.3 " " benzyl 309 " " " 3-F " " " 310
" " " 3-Cl " " " 311 " " " 3-CH.sub.3 " " " 312 " " " H " "
2-thienyl- methyl 313 i-C.sub.3 H.sub.7 H H 3-OCH.sub.3 CH.sub.2
##STR79## benzyl 314 " " " 3-F " " " 315 " " " 3-Cl " " " 316 " " "
3-CH.sub.3 " " " 317 CH.sub.3 " " H " " 3-phenyl- propyl 318 " " "
3-OCH.sub.3 " " 2-thienyl- methyl 319 " " " 3-F " " 2-thienyl-
methyl 320 " " " 3-Cl " " 2-thienyl- methyl 321 " " " 3-CH.sub.3 "
" 2-thienyl- methyl 322 CH.sub.2 CH.sub.2 CH.sub.2 " " 3-OCH.sub.3
" " 2-thienyl- methyl 323 " " " 3-F " " 2-thienyl- methyl 324 " " "
3-Cl " " 2-thienyl- methyl 325 " " " 3-CH.sub.3 " " 2-thienyl-
methyl 326 C.sub.2 H.sub.5 " " H " " 3-thienyl- methyl 327 CH.sub.3
" " 3-OCH.sub.3 " " 3-thienyl- methyl 328 " " " 3-F " " 3-thienyl-
methyl 329 " " " 3-Cl " " 3-thienyl- methyl 330 " " " 3-CH.sub.3 "
" 3-thienyl- methyl
__________________________________________________________________________
TABLE 2
__________________________________________________________________________
(Compound III) ##STR80## ##STR81## ##STR82## ##STR83## ##STR84##
##STR85## ##STR86##
__________________________________________________________________________
1 CH.sub.2 CH.sub.2 CH.sub.2 H double bond ##STR87## benzyl 2 " "
single bond ##STR88## " 3 " " CH " " 4 " " CH.sub.2 " " 5 " "
CHCH.sub.2 " " 6 " " (CH.sub.2).sub.2 " " 7 " " double bond
##STR89## 4-fluorobenzyl 8 " " single bond ##STR90## " 9 " " CH " "
10 " " CH.sub.2 " " 11 " " CHCH.sub.2 " " 12 " " (CH.sub.2).sub.2 "
" 13 " " double bond ##STR91## 3-fluorobenzyl 14 " " single bond
##STR92## " 15 " " CH " " 16 " " CH.sub.2 " " 17 " " CHCH.sub.2 " "
18 " " (CH.sub.2).sub.2 " " 19 CH.sub.2 CH.sub.2 CH.sub.2 H double
bond ##STR93## 2-fluorobenzyl 20 " " single bond ##STR94## " 21 " "
CH " " 22 " " CH.sub.2 " " 23 " " CHCH.sub.2 " " 24 " "
(CH.sub.2).sub.2 " " 25 " " double bond ##STR95## 4-methoxybenzyl
26 " " single bond ##STR96## " 27 " " CH.sub.2 " " 28 " " CH.sub.2
" " 29 " " CHCH.sub.2 " " 30 " " (CH.sub.2).sub.2 " " 31 " " double
bond ##STR97## 3-methoxybenzyl 32 " " single bond ##STR98## " 33 "
" CH " " 34 " " CH.sub.2 " " 35 " " CHCH.sub.2 " " 36 " "
(CH.sub.2).sub.2 " " 37 CH.sub.2 CH.sub.2 CH.sub.2 H double bond
##STR99## 4-hydroxybenzyl 38 " " single bond ##STR100## " 39 " " CH
" " 40 " " CH.sub.2 " " 41 " " CHCH.sub.2 " " 42 " "
(CH.sub.2).sub.2 " " 43 " " double bond ##STR101## 4-chlorobenzyl
44 " " single bond ##STR102## " 45 " " CH " " 46 " " CH.sub.2 " "
47 " " CHCH.sub.2 " " 48 " " (CH.sub.2).sub.2 " " 49 " " double
bond ##STR103## 3-chlorobenzyl 50 " " single bond ##STR104## " 51 "
" CH " " 52 " " CH.sub.2 " " 53 " " CHCH.sub.2 " " 54 " "
(CH.sub.2).sub.2 " " 55 CH.sub.2 CH.sub.2 CH.sub.2 H double bond
##STR105## 2-chlorobenzyl 56 " " single bond ##STR106## " 57 " " CH
" " 58 " " CH.sub.2 " " 59 " " CHCH.sub.2 " " 60 " "
(CH.sub.2).sub.2 " " 61 " " double bond ##STR107## 4-methylbenzyl
62 " " single bond ##STR108## " 63 " " CH " " 64 " " CH.sub.2 " "
65 " " CHCH.sub.2 " " 66 " " (CH.sub.2).sub.2 " " 67 " " double
bond ##STR109## 4-nitrobenzyl 68 " " single bond ##STR110## " 69 "
" CH " " 70 " " CH.sub.2 " " 71 " " CHCH.sub.2 " " 72 " "
(CH.sub.2).sub.2 " " 73 CH.sub.2 CH.sub.2 CH.sub.2 H double bond
##STR111## 4-trifluoromethylbenzyl 74 " " single bond ##STR112## "
75 " " CH " " 76 " " CH.sub.2 " " 77 " " CHCH.sub.2
" " 78 " " (CH.sub.2).sub.2 " " 79 " " double bond ##STR113##
sec-phenethyl 80 " " single bond ##STR114## " 81 " " CH " " 82 " "
CH.sub.2 " " 83 " " CHCH.sub.2 " " 84 " " (CH.sub.2).sub.2 " " 85 "
" double bond ##STR115## diphenylmethyl 86 " " single bond
##STR116## " 87 " " CH " " 88 " " CH.sub.2 " " 89 " " CHCH.sub.2 "
" 90 " " (CH.sub.2).sub.2 " " 91 CH.sub.2 CH.sub.2 CH.sub.2 H
double bond ##STR117## di(4-fluorophenyl)methyl 92 " " single bond
##STR118## " 93 " " CH " " 94 " " CH.sub.2 " " 95 " " CHCH.sub.2 "
" 96 " " (CH.sub.2).sub.2 " " 97 " " double bond ##STR119##
2-thienylmethyl 98 " " single bond ##STR120## " 99 " " CH " " 100 "
" CH.sub.2 " " 101 " " CHCH.sub.2 " " 102 " " (CH.sub.2).sub.2 " "
103 " " double bond ##STR121## 2-pyridylmethyl 104 " " single bond
##STR122## " 105 " " CH " " 106 " " CH.sub.2 " " 107 " " CHCH.sub.2
" " 108 " " (CH.sub.2).sub.2 " " 109 CH.sub.2 CH.sub.2 CH.sub.2 H
double bond ##STR123## 4-pyridylmethyl 110 " " single bond
##STR124## " 111 " " CH " " 112 " " CH.sub.2 " " 113 " " CHCH.sub.2
" " 114 " " (CH.sub.2).sub.2 " " 115 " " double bond ##STR125##
2-pyrimidinylmethyl 116 " " single bond ##STR126## " 117 " " CH " "
118 " " CH.sub.2 " " 119 " " CHCH.sub.2 " " 120 " "
(CH.sub.2).sub.2 " " 121 " " double bond ##STR127##
4-pyrimidinylmethyl 122 " " single bond ##STR128## " 123 " " CH " "
124 " " CH.sub.2 " " 125 " " CHCH.sub.2 " " 126 " "
(CH.sub.2).sub.2 " " 127 H H H CH.sub.2 ##STR129## benzyl 128 "
CH.sub.3 " " " " 129 " C.sub.2 H.sub.5 " " " " 130 " C.sub.3
H.sub.7 " " " " 131 " i-C.sub.3 H.sub.7 " " " " 132 " C.sub.4
H.sub.9 " " " " 133 " sec-C.sub.4 H.sub.9 " " " " 134 " C.sub.6
H.sub.13 " " " " 135 " C.sub.8 H.sub.17 " " " " 136 " C.sub.10
H.sub.21 " " " " 137 " Cl " " " " 138 " Br " " " " 139 " OCH.sub.3
" " " " 140 " OC.sub.2 H.sub.5 " " " " 141 CH.sub.3 CH.sub.3 " " "
" 142 C.sub.2 H.sub.5 " " " " " 143 C.sub.3 H.sub.7 " " " " " 144
i-C.sub.3 H.sub.7 " " " " " 145 C.sub.4 H.sub.9 CH.sub.3 H CH.sub.2
##STR130## benzyl 146 sec-C.sub.4 H.sub.9 " " " " " 147 i-C.sub.4
H.sub.9 " " " " " 148 C.sub.5 H.sub.11 " " " " " 149 C.sub.7
H.sub.15 " " " " " 150 C.sub.9 H.sub.19 " " " " " 151 Cl CH.sub.3 "
" " " 152 Br " " " " " 153 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 " "
" " 154 CH(CH.sub.3)CH.sub.2 CH.sub.2 " " " " 155 CH.sub.2
CH(CH.sub.3)CH.sub.2 " " " " 156 CH.sub.2 CH.sub.2 CH(CH.sub.3) " "
" " 157 CH.sub.2 CH.sub.2 CH(OH) " " " " 158 CH.sub.2 CH.sub.2
CH(OCH.sub.3) " " " " 159
CH.sub.2 CH.sub.2 CH(OC.sub.2 H.sub.5) " " " " 160 CH.sub.2
CH.sub.2 CH(OC.sub.3 H.sub.7) " " " " 161 CH.sub.2 CH.sub.2
CH(OCH.sub.2 CHCH.sub.2) " " " " 162 CH.sub.2 CH.sub.2 CH(OCH.sub.2
C.sub.6 H.sub.5) " " " " 163 CH.sub.2 CH.sub.2 CH(OCOH) " " " " 164
CH.sub.2 CH.sub.2 CH(OCOCH.sub.3) H CH.sub.2 ##STR131## benzyl 165
CH.sub.2 CH.sub.2 CH(OCOC.sub.2 H.sub.5) " " " " 166 CH.sub.2
CH.sub.2 CH(OCOC.sub.3 H.sub.7) " " " " 167 CH.sub.2 CH.sub.2
CH(OCOC.sub.5 H.sub.11) " " " " 168 CH.sub.2 CH.sub.2 CH(OCOC.sub.9
H.sub.19) " " " " 169 CH.sub.2 CH.sub.2 CH(OCOCH.sub.2 C.sub.6
H.sub.5) " " " " 170 CH.sub.2 CH.sub.2 CH(OCOC.sub.6 H.sub.5) " " "
" 171 CH.sub.2 CH.sub.2 CH(F) " " " " 172 CH.sub.2 CH.sub.2 CH(Cl)
" " " " 173 CH.sub.2 CH.sub.2 CH(Br) " " " " 174 CH.sub.2 CH.sub.2
C(F).sub.2 " " " " 175 CH(Br)CH.sub.2 CH(Br) " " " " 176 CH.sub.3
Cl " " " " 177 " Br " " " " 178 " CH.sub.2 OH " " " " 179 "
CH.sub.2 OCH.sub.3 " " " " 180 " CH.sub.2 OCOCH.sub.3 " " " " 181 "
CH.sub.2 F " " " " 182 " CH.sub.2 Cl " " " " 183 CH.sub.2 CH.sub.2
CH.sub.2 H CH.sub.2 ##STR132## 2-pyrimidinylmethyl 184 CH.sub.2
C(CH.sub.3).sub.2 CH.sub.2 " " " benzyl 185 CH.sub.2 CH.sub.2
CH(OC.sub.6 H.sub.5) " " " "
__________________________________________________________________________
In the formula (II), the compounds (IIa to e) wherein R.sup.4 is a
hydrogen atom can be prepared by [Preparation process 1-1],
[Preparation process 2-1], [Preparation process 3-1] or
[Preparation process 4-1], and in the formula (III), the compounds
(IIIa to e) wherein R.sup.4 is a hydrogen atom can be prepared by
[Preparation process 1-2], [Preparation process 2-2], [Preparation
process 3-2] or [Preparation process 4-2].
On the other hand, in the formula (II), the compound (IIf) wherein
R.sup.4 is an acyl group can be prepared by [Preparation process
5-1] and in the formula (III), the compound (IIIf) wherein R.sup.4
is an acyl group can be prepared by [Preparation process 5-2].
##STR133##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, X, Y and . .
. have the same meanings as described above and Z represents a
halogen atom)
In [Preparation process 1-1] or [Preparation process 1-2], the
compound (IIa) or (IIIa) is prepared by reacting the compound (IV)
or (VI) with the compound (V) in a 1- to 5-fold molar amount,
preferably a 1- to 2-fold molar amount in a solvent in the presence
or absence of an acid.
The solvent to be used is not particularly limited so long as it is
inert to the above reactions, and may include, for example,
alcohols such as methanol, ethanol, propanol, isopropanol, butanol,
etc.; aprotic polar solvents such as dimethylformamide, dimethyl
sulfoxide, dimethylacetamide, hexamethylphosphoric acid triamide,
etc.; halogenated hydrocarbons such as chloroform, carbon
tetrachloride, dichloroethane, etc.; esters such as ethyl acetate,
etc.; and nitriles such as acetonitrile, etc. Preferred are the
aforesaid alcohols, halogenated hydrocarbons and aprotic polar
solvents.
As the acid to be used, there may be mentioned, for example, a
Br.phi.nsted acid such as hydrochloric acid, sulfuric acid,
phosphoric acid, acetic acid, propionic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluene-sulfonic acid, etc.; and a Lewis
acid such as stannous chloride, stannic chloride, zinc chloride,
aluminum chloride, titanium tetrachloride, etc., preferably
hydrochloric acid, stannous chloride, stannic chloride and zinc
chloride. The amount to be used is generally a 0.01- to 10-fold
molar amount, preferably a 0.1- to 5-fold molar amount based on the
compound (V).
The reaction temperature is 0.degree. to 200.degree. C., preferably
the reaction is carried out in the range of 0.degree. to
150.degree. C. The reaction time varies depending on conditions
other than those described above, but the reaction is carried out
generally for 5 minutes to 24 hours, preferably for 10 minutes to
12 hours.
The compound (IV) is generally used as a free material, but a salt
with the Br.phi.nsted acid or a complex with the Lewis acid as
mentioned above may be also used. In that case, the reaction can
proceed smoothly without further adding the Br.phi.nsted acid or
Lewis acid as mentioned above to the reaction system.
Also, when the compound (IV) or (VI) wherein R.sup.5 is a hydroxy
group is reacted in the aforesaid alcohol in the presence of an
acid, as the formed compound (IIa) or (IIIa), in addition to the
compound wherein R.sup.5 is a hydroxy group, a compound (for
example, in the reaction in ethanol, a compound wherein R.sub.5 is
an ethoxy group) wherein R.sup.5 is an alkoxy group which can be
obtained by replacing the hydroxy group with an alcohol of the
solvent and a compound having a double bond which is a dehydrated
product can be obtained. ##STR134##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6 and p have the same
meanings as described above)
In [Preparation process 2-1] or [Preparation process 2-2], the
compound (IIb), (IIc), (IIIb) or (IIIc) is prepared by subjecting
the compound (VII) or (X) and the compound (VIII) or (IX) in a 1-
to 5-fold molar amount, preferably a 1- to 2-fold molar amount to
condensation reaction in a solvent in the presence of a base.
The solvent to be used is not particularly limited so long as it is
inert to the above reactions, and may include, for example,
alcohols such as methanol, ethanol, propanol, isopropanol, butanol,
etc.; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, etc.; aprotic polar solvents such as
dimethylformamide, dimethyl sulfoxide, dimethylacetamide, etc.;
nitriles such as acetonitrile, etc.; and esters such as ethyl
acetate, etc. Preferred are the above alcohols, ethers and
nitriles.
As the base to be used, there may be mentioned, for example, alkali
metal alkoxides such as sodium methoxide, sodium ethoxide,
potassium t-butoxide, etc.; alkyl lithiums such as butyl lithium,
t-butyl lithium, etc.; alkali metal hydrides such as sodium
hydride, lithium hydride, etc.; alkali metal amides such as sodium
amide, etc.; amines such as triethylamine, tributylamine,
diisopropylethylamine, pyridine, picoline, luridine, etc.; alkali
metal hydroxides such as sodium hydroxide, potassium hydroxide,
etc.; and alkali metal carbonates such as sodium carbonate,
potassium carbonate, etc. Preferred are the above alkali metal
alkoxides, alkyl lithiums, alkali metal hydrides and amines. The
amount to be used is generally a 1- to 10-fold molar amount,
preferably a 1- to 5-fold molar amount based on the compound (VII)
or (X).
The reaction temperature is -70.degree. to 150.degree. C.,
preferably the reaction is carried out in the range of -50.degree.
to 100.degree. C. The reaction time varies depending on conditions
other than those described above, but the reaction is carried out
generally for 15 minutes to 100 hours, preferably for 30 minutes to
72 hours. ##STR135##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6 and p have the same
meanings as described above)
In [Preparation process 3-1] or [Preparation process 3-2], the
compound (IId), (IIe), (IIId) or (IIIe) is prepared by subjecting
the compound (IIb), (IIc), (IIIb) or (IIIc) to catalytic reduction
with a hydrogen gas in a solvent in the presence of a catalyst or
to reduction by a reducing agent.
The solvent to be used when catalytic reduction with a hydrogen gas
is carried out is not particularly limited so long as it is inert
to the above reaction, and may include, for example, alcohols such
as methanol, ethanol, propanol, isopropanol, butanol, etc.; ethers
such as diethyl ether, tetrahydrofuran, dioxane, etc.; water; and
acetic acid. Preferred are the above alcohols. When the compound
(IIb), (IIc), (IIIb) or (IIIc) is not easily dissolved in the above
solvent, dissolution can be accelerated by a method of mixing these
solvents, adding a small amount of hydrochloric acid, etc., whereby
the reaction can be accelerated.
As the catalyst to be used, there may be mentioned, for example, a
noble metal type catalyst such as platinum oxide, palladium-carbon,
platinum-carbon, etc., preferably platinum oxide and
palladium-carbon. The amount of the catalyst to be used is
generally 0.01 to 50% by weight, preferably 0.1 to 50% by weight
based on the compound (IIb), (IIc), (IIIb) or (IIIc).
The hydrogen gas may be passed to the reaction mixture at normal
pressure or may be reacted in an autoclave under pressurization up
to 100 kg/cm.sup.2. The pressure is preferably normal pressure to
50 kg/cm.sup.2.
The reaction temperature is 0.degree. to 200.degree. C., preferably
the reaction is carried out in the range of 0.degree. to
150.degree. C. The reaction time varies depending on conditions
other than those described above, but the reaction is carried out
generally for 10 minutes to 24 hours, preferably for 15 minutes to
12 hours.
On the other hand, when reduction is carried out by using a
reducing agent, as the reducing agent, preferred is a reducing
agent used for reduction of an .alpha..beta.-unsaturated ketone,
such as metallic lithium-ammonia, triethylsilane-trifluoroacetic
acid, triphenyltin hydride, lithium aluminum hydride-cuprous
iodide, etc. These reactions can be carried out, for example, under
conditions described in "New Experimental Chemistry Lecture" edited
by the Japan Chemical Society, vol. 14 (I), p. 5. ##STR136##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6 X, Y, Z and .
. . have the same meanings as described above and R.sup.7
represents a protective group such as a t-butoxycarbonyl group, a
benzyloxycarbonyl group, an acetyl group, a trifluoroacetyl group,
a benzoyl group, a triphenylmethyl group and a methoxymethyl
group)
In [Preparation process 4-1] or [Preparation process 4-2], the
compound (IIa) or (IIIa) can be also prepared by reacting the
compound (IV') or (VI') having the protective group R.sup.7 with
the compound (V) to prepare the compound (II'a) or (III'a),
removing the protective group and then carrying out alkylation.
The protective group R.sup.7 may be any protective group generally
used as a protective group for an amino group, and there may be
mentioned, for example, a protective group such as a
t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group,
a trifluoroacetyl group, a benzoyl group, a triphenylmethyl group
and a methoxymethyl group.
The reactions for obtaining the compound (II'a) from the compounds
(IV') and (V) and the compound (III'a) from the compounds (VI') and
(V) can be carried out according to the same method as described
above in [Preparation process 1-1] and [Preparation process
1-2].
The deprotection reaction for obtaining the compound (XI) from the
compound (II'a) or the compound (XIII) from the compound (III'a)
can be carried out by suitably selecting from methods described in
literature (e.g. T. W. Greene, "Protective Groups in Organic
Synthesis" John Wiley & Sons), for example, a method using an
acid, an alkali or hydrogen reduction, etc.
In the alkylation reactions for obtaining the compound (IIa) from
the compound (XI) and the compound (IIIa) from the compound (XIII),
the solvent to be used is not particularly limited so long as it is
inert to the above reactions, and may include, for example, ketones
such as acetone, methyl ethyl ketone, etc.; ethers such as diethyl
ether, tetrahydrofuran, dioxane, etc.; alcohols such as methanol,
ethanol, propanol, isopropanol, butanol, etc.; aprotic polar
solvents such as dimethylformamide, dimethyl sulfoxide,
dimethylacetamide, hexamethylphosphoric acid triamide, etc.;
halogenated hydrocarbons such as chloroform, dichloromethane,
dichloroethane, etc. and others.
It is generally desired to carry out the above reactions in the
presence of a base. As the base, there may be mentioned alkali
metal carbonates such as sodium carbonate, potassium carbonate,
etc.; and amines such as triethylamine, tributylamine,
diisopropylethylamine, pyridine, picoline, etc.
The reaction temperature is 0.degree. to 150.degree. C., preferably
the reaction is carried out in the range of 0.degree. to
100.degree. C. The reaction time is generally 15 minutes to 72
hours, preferably the reaction is carried out for 30 minutes to 24
hours. ##STR137##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, X, Y, Z and .
. . have the same meanings as described above and R.sup.4'
represents the same acyl group described in R.sup.4)
In [Preparation process 5-1] or [Preparation process 5-2], the
compound (IIf) or (IIIf) is prepared by reacting the compound (IIa)
or (IIIa) with the acyl halide (XIV) in a 1- to 5-fold molar
amount, preferably a 1- to 2-fold molar amount in the presence of a
base.
The solvent to be used is not particularly limited so long as it is
inert to the above reactions, and may include, for example,
halogenated hydrocarbons such as methylene chloride, chloroform,
dichloroethane, etc.; aprotic polar solvents such as
dimethylformamide, dimethyl sulfoxide, dimethylacetamide,
hexamethylphosphoric acid triamide, etc.; esters such as ethyl
acetate, etc.; and nitriles such as acetonitrile, etc. Preferred
are halogenated hydrocarbons and aprotic polar solvents.
As the base to be used, there may be mentioned amines such as
triethylamine, tributylamine, diisopropylethylamine, pyridine,
picoline, lutidine, etc.; alkali metal carbonates such as sodium
carbonate, potassium carbonate, etc. and others. Preferred are
amines. The amount to be used is generally a 1- to 10-fold molar
amount, preferably a 1- to 5-fold molar amount based on the acyl
halide.
The reaction temperature is -70.degree. to 150.degree. C.,
preferably the reaction is carried out in the range of -50.degree.
to 100.degree. C. The reaction time varies depending on conditions,
but the reaction is carried out generally for 15 minutes to 100
hours, preferably for 30 minutes to 72 hours.
In the compound (II) or (III), when at least one of R.sup.1,
R.sup.2 and R.sup.3 has a functional group such as a hydroxy group,
an amino group, etc., these can be converted into an acyloxy group,
an acylamino group, etc., respectively, according to a known
method, for example, by subjecting it to acylation reaction. When
it has a nitro group, it can be converted into an amino group by
reduction reaction.
The compounds (VIII) and (IX) to be used in the above [Preparation
process 2-1] and [Preparation process 2-2] are known compounds or
compounds easily prepared from known compounds according to a
conventional method.
The compounds (V), (VII) and (X) to be used as starting materials
in [Preparation process 1-1], [Preparation process 1-2],
[Preparation process 2-1], [Preparation process 2-2], [Preparation
process 4-1] and [Preparation process 4-2] can be prepared easily
according to known methods (see Japanese Provisional Patent
Publication No. 203072/1982 and Japanese Provisional Patent
Publication No. 70/1987). The compounds (IV), (VI), (IV') and (VI')
to be used as starting materials in [Preparation process 1-1],
[Preparation process 1-2], [Preparation process 4-1] and
[Preparation process 4-2] can be prepared by [Preparation process
6-1], [Preparation process 6-2], [Preparation process 8-1],
[Preparation process 8-2], [Preparation process 9-1] and
[Preparation process 9-2] shown below. ##STR138##
(wherein R.sup.3, R.sup.6 and p have the same meanings as described
above and R.sup.8 represents a methyl group, an ethyl group or a
phenyl group) ##STR139##
(wherein R.sup.3 and p have the same meanings as described
above)
The condensation reactions of [Preparation process 6-1] and
[Preparation process 6-2] are carried out by the same methods as
described above in [Preparation process 2-1] and [Preparation
process 2-2], or carried out by a known method known as the
Horner-Wadsworth-Emmons reaction (see, for example, M. A.
Blanchette et at., Tetrahedron Letters, vol. 25, 2183).
In the reduction reactions of [Preparation process 6-1] and
[Preparation process 6-2], partial reduction reactions for
obtaining the compound (IVa) from the compound (XVIa), the compound
(IVc) from the compound (XVIb), the compound (VIa) from the
compound (XVIIIa) and the compound (VIc) from the compound (XVIIIb)
are carried out by a method of using stannous chloride, tin, zinc
or iron, preferably stannous chloride or tin under acidic
conditions or using zinc under neutral or alkaline conditions. As
the solvent to be used for these reactions, there may be mentioned,
in addition to alcohols such as methanol, ethanol, propanol, etc.,
acetonitrile, acetic acid, water, etc. Preferred are alcohols,
acetic acid and water. These may be used as a mixture. Further, as
the acid to be used, there may be mentioned mineral acids such as
hydrochloric acid, sulfuric acid and phosphoric acid or organic
acids such as acetic acid and propionic acid. Preferred are
hydrochloric acid, sulfuric acid and acetic acid. As the alkali,
there may be mentioned an alkali metal hydroxide such as sodium
hydroxide and potassium hydroxide. The reactions are carried out
generally at a temperature of 0.degree. to 200.degree. C.,
preferably in the range of 0.degree. to 150.degree. C. for 30
minutes to 72 hours, preferably 1 hour to 24 hours.
On the other hand, in the reduction reactions of [Preparation
process 6-1] and [Preparation process 6-2], simultaneous reduction
reactions of nitro groups and double bonds for obtaining the
compound (Ivb) from the compound (XVIa), the compound (IVd) from
the compound (XVIb), the compound (VIb) from the compound (XVIIIa)
and the compound (VId) from the compound (XVIIIb) are carried out
by the same methods as described above in [Preparation process 3-1]
and [Preparation process 3-2].
The nitro compounds (XVIa), (XVIb), (XVIIIa) and (XVIIIb) which are
intermediates in [Preparation process 6-1] and [Preparation process
6-2] and the compounds (IV') (i.e., IV'a, IV'b, IV'c and IV'd) and
the compounds (VI') (i.e., VI'a, VI'b, VI'c and VI'd) which are
starting materials in [Preparation process 4-1] and [Preparation
process 4-2] can be also prepared by [Preparation process 7-1] and
[Preparation process 7-2] shown below. ##STR140##
(wherein R.sup.3, R.sup.6, R.sup.7, Z and p have the same meanings
as described above) ##STR141##
(wherein R.sup.3, R.sup.7 and p have the same meanings as described
above)
The condensation reactions of [Preparation process 7-1] and
[Preparation process 7-2] are carried out by the same methods as
described above in [Preparation process 6-1] and [Preparation
process 6-2], and the deprotection reactions are carried out in the
same manner as in [Preparation process 4-1] and [Preparation
process 4-2], by suitably selecting a known method of using an
acid, an alkali or hydrogen reduction, etc. Also, the N-alkylation
reaction by the compound (XII) is carried out by the same methods
as described above in [Preparation process 4-1] and [Preparation
process 4-2], and the reduction reactions of the compounds (XVI'a),
(XVI'b), (XVIII'a) and (XVIII'b) can be carried out by the same
methods as described above in [Preparation process 6-1] and
[Preparation process 6-2]. ##STR142##
(wherein R.sup.3, R.sup.6 and p have the same meanings as described
above and R.sup.9 represents a protective group such as a
t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group,
a trifluoroacetyl group and a benzoyl group) ##STR143##
(wherein R.sup.3, R.sup.9 and p have the same meanings as described
above)
In [Preparation process 8-1] or [Preparation process 8-2], the
compound (XXIIa), (XXIId), (XXIVa) or (XXIVd) is prepared by
subjecting the compound (XXI) or (XXIII) with the compound (VIII)
or (IX) in a 1- to 5-fold molar amount, preferably a 1- to 2-fold
molar amount to condensation reaction in a solvent in the presence
of a strong base.
R.sup.9 as the protective group is not particularly limited so long
as it is stable under these reaction conditions, and preferred are
a t-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl
group, a trifluoroacetyl group, a benzoyl group, etc.
As the solvent to be used, there may be mentioned ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.;
aliphatic and aromatic hydrocarbons such as pentane, hexane,
cyclohexane, benzene, toluene, etc.; and aprotic polar solvents
such as hexamethylphosphoric acid triamide, dimethyl sulfoxide,
etc. Also, a mixture of these solvents may be used.
As the strong base to be used, preferred are alkyl lithiums such as
n-butyl lithium, t-butyl lithium, etc.; alkali metal amides such as
lithium diisopropylamide, lithium ditrimethylsilylamide, sodium
amide, etc.; and alkali metal hydrides such as sodium hydride,
potassium hydride, etc. The amount to be used is generally a 1- to
5-fold molar amount, preferably a 2- to 3-fold molar amount based
on the compound (XXI) or (XXIII).
The reaction temperature is -70.degree. to 100.degree. C.,
preferably the reaction is carried out in the range of -70.degree.
to 50.degree. C.
The dehydration reactions of [Preparation process 8-1] and
[Preparation process 8-2] are generally carried out by suitably
selecting from various known methods used when an olefin is
synthesized from an alcohol. There may be mentioned, for example, a
dehydration method under acidic conditions using an inorganic acid
such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.; or
an organic acid such as p-tolunesulfonic acid, benzenesulfonic
acid, etc., or a dehydration method in the coexistence of a
dehydrating agent such as thionyl chloride, phosphorus oxychloride,
methanesulfonic acid chloride, methanesulfonic anhydride, acetic
anhydride, etc. and an organic base such as pyridine, picoline,
lutidine, 1,8-diazabicyclo[5.4.0.]-7-undecene, triethylamine, etc.
Particularly when the protective group R.sup.9 is unstable under
acidic conditions, the latter method is preferred.
In the above dehydration reactions, as in the examples of the
compounds (XXIIe) and (XXIIf), and (XXIVe) and (XXIVf), isomers
having the double bond at different positions may be produced.
These may be separated and used or may be used as a mixture when
they are used for the reduction reactions.
The reduction reactions of [Preparation process 8-1] and
[Preparation process 8-2] are carried out by the same methods as
described above in [Preparation process 3-1] and [Preparation
process 3-2].
By deprotecting the above compounds (XXIIa), (XXIIb), (XXIIc),
(XXIId), (XXIIe), (XXIIf), (XXIIg), (XXIVa), (XXIVb), (XXIVc),
(XXIVd), (XXIVe), (XXIVf) and (XXIVg), the compounds (IVe), (IVa),
(IVb), (IVf), (IVc), (IVg), (IVd), (VIe), (VIa), (VIb), (VIf),
(VIc), (VIg) and (VId) are prepared, respectively. The deprotection
reactions are carried out by the same methods as described above in
[Preparation process 4-1] and [Preparation process 4-2].
##STR144##
(wherein R.sup.3, R.sup.6, R.sup.7, R.sup.9, Z and p have the same
meanings as described above) ##STR145##
(wherein R.sup.3, R.sup.6, R.sup.7, R.sup.9, Z and p have the same
meanings as described above)
In [Preparation process 9-1] and [Preparation process 9-2], the
condensation reactions, dehydration reactions and reduction
reactions are carried out by the same methods as described in
[Preparation process 8-1] and [Preparation process 8-2].
R.sup.7 and R.sup.9 as protective groups may be different or may be
the same. The respective compounds obtained in the respective
reactions of [Preparation process 9-1] and [Preparation process
9-2] are supplied to the deprotection reactions, respectively. In
this case, by suitably selecting the kinds of the two protective
groups R.sup.7 and R.sup.9 or suitably selecting deprotection
conditions, either one of R.sup.7 and R.sup.9 can be selectively
removed. Also, both of them can be removed simultaneously. The
selections of these R.sup.7 and R.sup.9 and deprotection conditions
can be carried out by referring to literature, for example, T. W.
Greene, "Protective Groups in Organic Synthesis" John Wiley &
Sons.
The compounds (XXVa), (XXVIa), (XXVb), (XXVIb), (XXVc), (XXVIc),
(XXVd), (XXVId), (XXVe), (XXVIe), (XXVf), (XXVIf), (XXVg), (XXVIg),
(XXVIIa), (XXVIIIa), (XXVIIb), (XXVIIIb), (XXVIIc), (XXVIIIc),
(XXVIId), (XXVIIId), (XXVIIe), (XXVIIIe), (XXVIIf), (XXVIIIf),
(XXVIIg) and (XXVIIIg) thus obtained can be converted into (XXIIa),
(IVe), (XXIIb), (IVa), (XXIIc), (IVb), (XXIId), (IVf), (XXIIe),
(IVc), (XXIIf), (IVg), (XXIIg), (IVd), (XXIVa), (VIe), (XXIVb),
(VIa), (XXIVc), (VIb), (XXIVd), (VIf), (XXIVe), (VIc), (XXIVf),
(VIg), (XXIVg) and (VId), respectively, by subjecting to alkylation
using the compound (XII) (R.sup.3 -Z) by the same methods as
described above in [Preparation process 4-1] and [Preparation
process 4-2], respectively.
After completion of the reactions, the desired compounds of the
respective reactions can be obtained by treating the reaction
mixtures according to a conventional method and further can be
purified by using a conventional purification means such as
recrystallization, column chromatography, etc., if necessary. The
compounds of the formula (I), the formula (II) and the formula
(III) of the present invention are converted into desired salts
according to a conventional method, if necessary.
In the compounds of the formula (I), the formula (II) and the
formula (III) thus prepared, optical isomers or geometric (cis and
trans or E and Z) isomers may exist. In that case, by carrying out
the above reactions by using starting compounds which are optically
resolved or separated as desired, optical isomers or geometric
isomers of the corresponding desired compounds can be obtained.
Also, by treating a mixture of optical isomers or geometric isomers
according to a conventional optical resolution method or separation
method, the respective isomers can be obtained.
In the formula (I), the formula (II) and the formula (III), all of
optical isomers, geometric isomers and mixtures thereof are
represented by the same formulae, but the respective isomers and
mixtures thereof are included in the present invention as a matter
of course.
BEST MODE FOR PRACTICING THE INVENTION
In the following, the present invention is described in detail by
showing Examples, but the scope of the present invention is not
limited by these.
EXAMPLE 1
(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]
aniline (Compound II-199 in Table 1)
1.27 g of 4-[3-(1-benzylpiperidin-4-yl)propenoyl]-nitrobenzene was
added to a mixed solution of 10 ml of acetic acid and 2 ml of
hydrochloric acid, and then 1.38 g of stannous chloride was added
thereto under ice cooling. The mixture was stirred for 24 hours
while further adding 0.69 g of stannous chloride twice during the
reaction. The solvent was removed under reduced pressure to obtain
a crude product of
(E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline. Then, this was
dissolved in 15 ml of ethanol, and to the solution was added 0.67 g
of 4-chloro-5,6-dimethylpyrimidine. Subsequently, the mixture was
reacted by heating at 60.degree. C. for 30 minutes. The reaction
mixture was neutralized by adding a 28% sodium methylate-methanol
solution under cooling, solids were removed by filtration, and then
the filtrate was consensed under reduced pressure. The obtained
residue was applied to silica gel column chromatography to obtain
1.02 g of the title compound as pale yellow powder.
m.p. 188.degree. to 190.degree. C. (decomposed)
Mass; m/z=426 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.45 to 1.87 (4H, m), 1.96 to 2.13 (2H,
m), 2.13 to 2.40 (1H, m), 2.22 (3H, s), 2.49 (3H, s), 2.86 to 3.02
(2H, m), 3.52 (2H, s), 6.62 (1H, s, br), 6.87 (1H, d, J=15.6 Hz),
7.03 (1H, dd, J=15.6 Hz, J=6.5 Hz), 7.18 to 7.43 (5H, m), 7.74 (2H,
d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.58 (1H, s)
EXAMPLE 2
N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]anili
ne (Compound II-150 in Table 1)
0.82 g of
(E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]
aniline obtained in Example 1 was added to a mixed solvent of 30 ml
of ethanol and 40 ml of dioxane, and then 0.05 g of platinum oxide
was added thereto. The mixture was stirred in a hydrogen stream at
room temperature for 3.5 hours. After the catalyst was removed by
filtration, the filtrate was condensed under reduced pressure. The
obtained residue was applied to silica gel column chromatography to
obtain 0.39 g of the title compound as pale yellow powder.
m.p. 168.degree. to 170.degree. C.
Mass; m/z =428 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.20 to 1.46 (3H, m), 1.60 to 1.85 (4H,
m), 1.85 to 2.07 (2H, m), 2.22 (3H, s), 2.49 (3H, s), 2.83 to 3.04
(4H, m), 3.50 (2H, s), 6.60 (1H, s, br), 7.20 to 7.40 (5H, m), 7.72
(2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.58 (1H, s)
EXAMPLE 3
N-(5-chloro-6-methylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propanoyl
]aniline.multidot.2HCl (2HCl salt of Compound II-160 in Table
1)
0.29 g of N- (5-chloro-6-methylpyrimidin-4-yl) -4- [3-
(1-benzylpiperidin-4-yl)propanoyl]aniline obtained in the same
manner as in Example 1 was dissolved in a mixed solvent of 10 ml of
ethyl acetate and 5 ml of ethanol, and a hydrogen chloride
gas-saturated ethyl acetate solution was added to the mixture until
the pH became 3. Crystals precipitated were collected by filtration
and dried to obtain 0.21 g of the title compound as white
powder.
(as 1/2H.sub.2 O adduct)
m.p. 217.degree. to 220.degree. C.
Mass; m/z=448 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.70 to 1.90 (7H, m), 2.71
(3H, s), 2.82 to 3.23 (4H, m), 3.34 to 3.42 (2H, m), 4.28 (2H, d,
J=4.9 Hz), 7.43 to 7.46 (3H, m), 7.67 to 7.69 (2H, m), 7.83 (2H, d,
J=8.8 Hz), 8.00 (2H, d, J=8.8 Hz), 8.71 (1H, s), 10.24 (1H, s),
11.15 (1H, s, br)
In the same manner as in Example 1, Example 2 or Example 3, the
following compounds were synthesized.
EXAMPLE 4
(E) -N- (5-chloro-6-methylpyrimidin-4-yl )
-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline (Compound II-162 in
Table 1)
White powder
m.p. 164.degree. to 166.degree. C.
Mass; m/z=446 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.49 to 1.70 (2H, m), 1.73 to 1.88 (2H,
m), 1.98 to 2.10 (2H, m), 2.18 to 2.36 (1H, m), 2.59 (3H, s), 2.90
to 2.98 (2H, m), 3.52 (2H, s), 6.87 (1H, d, J=15 to 16 Hz), 7.04
(1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 7.41 (1H, s), 7.79 (2H, d,
J=8 to 9 Hz), 7.98 (2H, d, J=8 to Hz), 8.58 (1H, s)
EXAMPLE 5
N-(6-chloropyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline.m
ultidot.HCl (HCl salt of Compound II-146 in Table 1)
(as 1/2H.sub.2 O adduct)
Pale yellow powder
m.p. 246.degree. to 260.degree. C. (decomposed)
Mass; m/z=434 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.40 to 1.72 (4H, m), 1.72
to 2.03 (3H, m), 2.77 to 3.20 (6H, m), 4.22 (2H, d, J=4.9 Hz), 6.95
(1H, s), 7.38 to 7.49 (3H, m), 7.38 to 7.63 (2H, m), 7.83 (2H, d,
J=8.8 Hz ), 7.93 (2H, d, J=8.8 Hz ), 8.52 (1H, s ), 10.05 (1H, br),
10.28 (1H, s)
EXAMPLE 6
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpiperidin-
4-yl)propenoyl]aniline (Compound II-5 in Table 1)
Pale yellow powder
m.p. 212.degree. to 214.degree. C.
Mass; m/z=438 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.46 to 1.87 (4H, m), 1.93 to 2.38 (5H,
m), 2.78 to 3.06 (6H, m), 3.52 (2H, s), 6.61 (1H, s, br), 6.87 (1H,
d, J=15.6 Hz), 7.04 (1H, dd, J=15.6 Hz, J=6.4 Hz), 7.20 to 7.40
(5H, m), 7.77 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz ), 8.65 (1H,
s )
EXAMPLE 7
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)
propanoyl]aniline (Compound II-2 in Table 1)
Pale yellow powder
m.p. 203.degree. to 205.degree. C.
Mass; m/z=440 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.23 to 1.41 (3H, m), 1.63 to 1.77 (4H,
m), 1.88 to 1.99 (2H, m), 2.14 to 2.26 (2H, m), 2.78 to 3.07 (8H,
m), 3.49 (2H, s), 6.49 (1H, s), 7.20 to 7.30 (2H, m), 7.20 to 7.26
(3H, m), 7.76 (2H, d, J=8.8 Hz), 9.96 (2H, d, J=8.8 Hz ), 8.65 (1H,
s )
EXAMPLE 8
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-benzylpiperidin-4-yl)
propanoyl]aniline. 2HCl (2HCl salt of Compound II-2 in Table 1)
(as H.sub.2 O adduct)
Grayish white crystal
m.p. 198.degree. to 201.degree. C. (decomposed)
Mass; m/z=440 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.52 to 2.21 (7H, m), 2.20
to 2.42 (2H, m), 2.68 to 3.55 (10H, m), 4.21 (2H, d, J=4.9 Hz),
7.38 to 7.52 (3H, m), 7.60 to 7.80 (2H, m), 7.80 to 8.03 (4H, m),
8.60 (1H, s), 11.53 to 11.80 (1H, m, br)
EXAMPLE 9
(E)-N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)prop
enoyl]aniline (Compound II-175 in Table 1)
White crystal
m.p. 171.degree. to 172.degree. C.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 to 2.15 (10H, m), 2.18 to 2.36 (1H,
m), 2.56 to 2.60 (2H, m), 2.82 to 2.88 (2H, m), 2.92 to 3.13 (2H,
m), 3.55 (2H, s), 6.56 (1H, s), 6.87 (1H, d, J=15.6 Hz), 7.04 (1H,
dd, J=6.4 Hz, J=15.6 Hz), 7.25 to 7.35 (5H, m), 7.77 (2H, d, J=8.8
Hz), 7.97 (2H, d, J=8.8 Hz), 8.60 (1H, s)
EXAMPLE 10
N-(5,6,7,8-tetrahydroquinazolin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propano
yl]aniline (Compound II-163 in Table 1)
(as 3/4H.sub.2 O adduct)
White crystal
m.p. 156.degree. to 157.degree. C.
Mass (CI); m/e=455 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.22 to 1.44 (3H, m), 1.61 to 1.74 (4H,
m), 1.90 to 2.00 (6H, m), 2.52 to 2.58 (2H, m), 2.79 to 2.98 (6H,
m), 3.48 (2H, s), 6.52 (1H, s), 7.25 to 7.32 (5H, m), 7.74 (2H, d,
J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.59 (1H, s)
EXAMPLE 11
(E)-N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzyl
piperidin-4-yl)propenoyl]aniline (Compound II-173 in Table 1)
(as 1/4H.sub.2 O adduct)
White crystal
m.p. 193.degree. to 195.degree. C. (decomposed)
Mass; m/z=468 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.50 to 1.82 (4H, m), 2.00 to 2.38 (4H,
m), 2.40 to 2.56 (1H, m), 2.64 to 2.80 (1H, m), 2.90 to 3.12 (3H,
m), 3.54 (2H, s), 3.58 (3H, s), 4.72 to 4.77 (1H, m), 6.59 (1H, s),
6.87 (1H, d, J=15.6 Hz ), 7.04 (1H, dd, J=6.4 Hz, 15.6 Hz), 7.26 to
7.34 (5H, m), 7.79 (2H, d, J=8.8 Hz ), 7.97 (2H, d, J=8.8 Hz), 8.75
(1H, s)
EXAMPLE 12
N-(7-methoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpipe
ridin-4-yl)propanoyl]aniline (Compound II-168 in Table 1)
(as 1/4H.sub.2 O adduct)
White crystal
m.p. 178.degree. to 180.degree. C.
Mass; m/z=470 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.19 to 1.45 (3H, m), 1.60 to 1.81 (4H,
m), 1.88 to 2.01 (2H, m), 2.07 to 2.24 (1H, m), 2.39 to 2.60 (1H,
m), 2.64 to 2.78 (1H, m), 2.85 to 3.02 (5H, m), 3.48 (2H, s), 3.58
(3H, s), 4.71 to 4.76 (1H, m), 6.52 (1H, s), 7.21 to 7.28 (5H, m),
7.76 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz)
EXAMPLE 13
(E)-N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-yl)-4-[3-(1-benzylpip
eridin-4-yl)propenoyl]aniline (Compound II-188 in Table 1)
Pale yellow powder
Mass ; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.47 to 1.90 (4H, m), 1.96
to 2.16 (2H, m), 1.86 to 2.16 (1H, m), 2.16 to 2.76 (3H, m), 2.76
to 3.23 (4H, m), 3.54 (2H, s), 5.70 to 5.78 and 5.96 to 6.06 (total
1H, each m), 6.89 (1H, d, J=15 to 16 Hz), 7.02 (1H, dd, J=15 to 16
Hz, J=5 to 6 Hz), 7.18 to 7.40 (5H, m), 7.86 to 8.04 (4H, m), 8.46
(1H, s), 8.74 (1H, s)
EXAMPLE 14
N-(7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperi
din-4-yl)propanoyl]aniline.multidot.2HCl (2HCl salt of Compound
II-183 in Table 1)
(as 1/2H.sub.2 O adduct)
White crystal
m.p. 173.degree. to 175.degree. C.
Mass; m/z=458 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.55 to 1.98 (7H, m), 2.16
to 2.80 (2H, m), 2.80 to 3.47 (8H, m), 4.30 (2H, d, J=4.9 Hz), 5.95
to 6.02 and 6.20 to 6.31 (total 1H, each m), 7.36 to 7.53 (3H, m),
7.59 to 7.76 (2H, m), 7.90 to 8.12 (4H, m), 8.88 (1H, s), 10.70
(1H, s), 10.88 (1H, br)
EXAMPLE 15
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-methoxybenzyl
)piperidin-4-yl]propenoyl}aniline (Compound II-29 in Table 1)
(as 1/2H.sub.2 O adduct)
White powder
m.p. 198.degree. to 199.5.degree. C.
Mass; m/z=468 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.50 to 1.68 (2H, m), 1.76
to 1.82 (2H, m), 2.00 to 2.28 (5H, m), 2.88 to 3.04 (6H, m), 3.47
(2H, s), 3.80 (3H, s), 6.80 to 6.95 (3H, m), 7.01 (1H, dd, J=15.1
Hz, J=6.4 Hz), 7.23 (2H, d, J=8.3 Hz), 7.57 (1H, s), 7.84 (2H, d,
J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.61 (1H, s)
EXAMPLE 16
(E)-N-(5,6-diethylpyrimidin-4-yl)-4-[3-(1-benzyl-piperidin-4-yl)propenoyl]a
niline (Compound II-200 in Table 1)
Pale yellow powder
Mass (CI); m/z=455 (M++i)
NMR (.delta., CDCl.sub.3); 1.20 to 1.38 (6H, m), 1.46 to 1.88 (4H,
m), 1.96 to 2.16 (2H, m), 2.15 to 2.40 (1H, m), 2.60 to 2.84 (4H,
m), 2.88 to 3.02 (2H, m), 3.51 (2H, s), 6.71 (1H, s, br), 6.88 (1H,
d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz), 7.20
to 7.45 (5H, m), 7.35 (2H, d, J=8 to 9 Hz), 7.97 (2H, d, J=8 to 9
Hz), 8.64 (1H, s)
EXAMPLE 17
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)
piperidin-4-yl]propenoyl}aniline (Compound II-11 in Table 1)
(as 1/2H.sub.2 O adduct)
White powder
m.p. 209.degree. to 210.5.degree. C.
Mass; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.52 to 1.64 (2H, m), 1.80 to 1.84 (2H,
m), 2.05 to 2.10 (2H, m), 2.13 to 2.22 (2H, m), 2.23 to 2.31 (1H,
m), 2.90 to 3.02 (6H, m), 3.49 (2H, s), 6.90 (1H, d, J=15.1 Hz),
6.92 to 7.03 (3H, m), 7.28 to 7.30 (2H, m), 7.85 (1H, s), 7.88 (2H,
d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.60 (1H, s)
EXAMPLE 18
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(4-fluorobenzyl)pipe
ridin-4-yl]propanoyl}aniline (Compound II-8 in Table 1)
(as 1/2H.sub.2 O adduct)
Pale yellow powder
m.p. 179.degree. to 181.degree. C.
Mass; m/z=458 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.29 to 1.45 (3H, m), 1.66 to 1.80 (4H,
m), 1.94 to 2.10 (2H, m), 2.15 to 2.26 (2H, m), 2.82 to 3.05 (8H,
m), 3.56 (2H, s, br), 6.46 (1H, s), 6.96 to 7.05 (2H, m), 7.25 to
7.36 (2H, m), 7.78 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.66
(1H, s)
EXAMPLE 19
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(3-fluorobenzyl)
piperidin-4-yl]propenoyl}aniline (Compound II-17 in Table 1)
White powder
m.p. 210.degree. to 211.degree. C.
Mass (CI); m/z=457 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.51 to 1.85 (4H, m), 2.02 to 2.30 (5H,
m), 2.83 to 3.06 (6H, m), 3.52 (2H, s), 6.46 (1H, s), 6.89 (1H, d,
J=15.6 Hz), 6.95 to 7.12 (4H, m), 7.23 to 7.35 (1H, m), 7.78 (2H,
d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz ), 8.66 (1H, s)
EXAMPLE 20
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(3-fluorobenzyl)pipe
ridin-4-yl]propanoyl)aniline.multidot.2HCl (2HCl salt of Compound
II-14 in Table 1)
(as 3/2H.sub.2 O adduct)
White powder
m.p.>252.degree. C. (decomposed)
Mass (CI); 459 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.40 (3H, m), 1.54 to 1.77 (4H,
m), 1.89 to 2.02 (2H, m), 2.15 to 2.25 (2H, m), 2.82 to 2.91 (4H,
m), 2.91 to 3.05 (4H, m), 3.47 (2H, s), 6.45 (1H, s), 6.89 to 6.96
(1H, m), 7.02 to 7.11 (2H, m), 7.22 to 7.28 (1H, m), 7.76 (2H, d,
J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.65 (1H, s)
EXAMPLE 21
4-[1-Oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H
-cyclopenta[d]pyrimidine (Compound III-3 in Table 2)
Under ice cooling, 1.70 g of a 28% sodium
methoxide.multidot.methanol solution was added to 1.96 g of
4-(1-oxoindan-5-yl)amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine
dissolved in tetrahydrofuran, and then 1.80 g of
1-benzyl-4-formylpiperidine was added dropwise thereto. After the
mixture was stirred for 1.5 hours, a saturated saline solution was
added to the reaction mixture, and the mixture was extracted with
chloroform. The extract was dried over anhydrous sodium sulfate and
condensed under reduced pressure. The obtained residue was applied
to silica gel column chromatography and then recrystallized from
chloroform to obtain 1.35 g of the title compound as pale yellow
crystal.
(as 1/2H.sub.2 O adduct)
m.p.>260.degree. C. (decomposed)
Mass; m/z=450 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.45 to 1.85 (4H, m), 1.96 to 2.46 (5H,
m), 2.80 to 3.10 (6H, m), 3.56 (2H, s), 3.70 (2H, s), 6.55 (1H, s),
6.70 (1H, d, J=9.8 Hz), 7.24 to 7.41 (6H, m), 7.82 (1H, d, J=5.3
Hz), 8.18 (1H, s), 8.66 (1H, s)
EXAMPLE 22
4-[1-Oxo-2-(1-benzylpiperidin-4-yl)methylindan-5-yl]amino-5,6-dihydro-7H-cy
clopenta[d]pyrimidine (Compound III-4 in Table 2)
0.53 g of platinum oxide was added to 1.35 g of
4-[1-oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7
H-cyclopenta[d]pyrimidine dissolved in a mixed solution of 60 ml of
tetrahydrofuran, 60 ml of ethanol and 1 ml of acetic acid, and the
mixture was stirred under a hydrogen stream at room temperature for
8 hours. After the catalyst was removed by filtration, the filtrate
was condensed. The obtained residue was applied to silica gel
column chromatography to obtain 1.31 g of the title compound as
pale yellow powder.
m.p. 200.degree. to 202.degree. C.
Mass; m/z=452 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.18 to 2.12 (9H, m), 2.12 to 2.30 (2H,
m), 2.62 to 3.08 (8H, m), 3.25 to 3.44 (1H, m), 3.55 (2H, s), 6.49
(1H, s), 7.20 to 7.41 (6H, m), 7.71 (1H, d, J=8.3 Hz), 8.10 (1H, d,
J=1 to 2 Hz), 8.66 (1H, s)
EXAMPLE 23
N-(5-ethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline
(Compound II-205 in Table 1)
To 10 ml of ethanol were added 0.23 g of
4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of
4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol
solution of hydrochloric acid (containing 0.071 g of hydrochloric
acid), the mixture was reacted under reflux for 2 hours. After
cooling, a 28% sodium methylate-methanol solution was added to the
reaction mixture to make it alkaline, and then the mixture was
condensed under reduced pressure. The obtained residue was applied
to silica gel column chromatography to obtain 0.18 g of the title
compound as pale yellow crystal.
m.p. 136.5.degree. to 138.degree. C.
Mass (CI); m/z=429 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.43 (3H, m), 1.37 (3H, t, J=7.3
Hz), 1.56 to 1.80 (4H, m), 1.87 to 2.05 (2H, m), 2.61 (2H, q, J=7.3
Hz), 2.81 to 3.00 (4H, m), 3.51 (2H, s), 6.63 (1H, s, br), 7.18 to
7.37 (5H, m), 7.77 (2H, d, J=9.2 Hz), 7.98 (2H, d, J=9.2 Hz), 8.27
(1H, s), 8.71 (1H, s)
EXAMPLE 24
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-nitrobenzyl)piper
idin-4-yl]propanoyl}aniline (Compound II-242 in Table 1)
(1)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3(1-acetylpiperidin-4-yl
)propanoyl]aniline
To 80 ml of chloroform were added 4.53 g of
4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline and 3.83 g of
4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding
10 ml of a chloroform solution of hydrochloric acid (containing 0.9
g of hydrochloric acid), the mixture was refluxed under heating for
5 hours. After completion of the reaction, a 28% sodium methoxide
was added to the mixture under ice cooling to make it alkaline and
then the solvent was removed by distillation under reduced
pressure. The obtained residue was applied to silica gel column
chromatography to obtain 6.16 g of the title compound as brown
powder.
Mass; m/z=392 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.00 to 1.27 (2H, m), 1.52
to 1.87 (5H, m), 2.05 (3H, s), 2.03 to 2.23 (2H, m), 2.45 to 2.61
(2H, m), 2.87 to 3.11 (6H, m), 3.76 to 3.89 (1H, m), 4.46 to 4.58
(1H, m), 7.86 to 7.96 (4H, m), 8.51 (1H, s), 8.70 (1H, s)
(2)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl)propan
oyl]aniline.multidot.2HCl salt
30 ml of conc. hydrochloric acid was added to 6.16 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-acetylpiperidin-4-y
l)propanoyl]aniline, and after refluxing under heating for 7 hours,
the mixture was condensed under reduced pressure. The obtained
residue was washed with methanol to obtain 3.38 g of the title
compound as yellow powder.
Mass; m/z=350 (M.sup.+)
NMR (.delta., CD.sub.3 OD); 1.36 to 1.56 (2H, m), 1.64 to 1.83 (3H,
m), 1.95 to 2.09 (2H, m), 2.92 to 3.24 (8H, m), 3.35 to 3.46 (2H,
m), 7.08 to 7.25 (1H, m), 7.90 (2H, d, J=9.2 Hz), 8.08 (2H, d,
J=9.2 Hz), 8.75 (1H, s) (3)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-{3-[1(2-nitrobenzyl)piperid
in-4-yl]acetyl}aniline
30 ml of acetone, 7.12 g of potassium carbonate and 0.62 g of
2-nitrobenzyl bromide were added to 1.00 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(piperidin-4-yl]propan
oyl]aniline.multidot.2HCl salt, and the mixture was stirred at room
temperature for 2 hours and allowed to stand overnight. Then, after
separating the solid by filtration and removing the solvent by
distillation under reduced pressure, the obtained residue was
applied to silica gel column chromatography to obtain 0.72 g of the
title compound as white powder.
m.p. 164.degree. to 166.degree. C.
Mass (SIMS); m/z=486 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.16 to 1.40 (3H, m), 1.52 to 1.77 (4H,
m), 1.94 to 2.08 (2H, m), 2.09 to 2.27 (2H, m), 2.72 to 3.06 (8H,
m), 3.75 (2H, s), 6.47 (1H, s), 7.32 to 7.43 (1H, m), 7.48 to 7.59
(1H, m), 7.60 to 7.68 (1H, m), 7.76 (2H, d, J=8.5 Hz), 7.74 to 7.83
(1H, m), 7.96 (2H, d, J=9.2 Hz), 8.65 (1H, s)
EXAMPLE 25
N-(5-methylpyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)acetyl]aniline
(Compound II-220 in Table 1)
To 70 ml of chloroform were added 7.00 g of
4-[(1-benzylpiperidin-4-yl)acetyl]aniline.multidot.2HCl salt and
8.38 g of 4-chloro-5-methylpyrimidine, and after further adding 10
ml of an ethanol solution of hydrochloric acid (containing 1.7 g of
hydrochloric acid), the mixture was reacted under reflux for 5
hours. After the reaction, a 28% sodium methylate-methanol solution
was added to the reaction mixture to make it alkaline and then the
mixture was condensed under reduced pressure. The obtained residue
was applied to silica gel column chromatography to obtain 5.30 g of
the title compound as pale yellow crystal.
m.p. 211.degree. to 213.degree. C.
Mass; m/z=400 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.26 to 1.47 (2H, m), 1.63 to 1.80 (3H,
m), 1.89 to 2.08 (2H, m), 2.25 (3H, s), 2.76 to 2.93 (4H, m), 3.48
(2H, s), 6.58 (1H, s, br), 7.17 to 7.38 (5H, m), 7.78 (2H, d, J=8.6
Hz), 7.97 (2H, d, J=8.6 Hz), 8.24 (1H, s), 8.70 (1H, s)
EXAMPLE 26
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)a
cetyl]aniline (Compound II-1 in Table 1)
(1)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)
acetyl]aniline
To 50 ml of chloroform were added 6.63 g of
4-[(1-acetylpiperidin-4-yl)acetyl]aniline.multidot.trifluoroacetate
and 3.01 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and
after adding 10 ml of a chloroform solution of hydrochloric acid
(containing 0.6 g of hydrochloric acid), the mixture was reacted
under reflux for 3 hours. After the reaction, a 28% sodium
methylate-methanol solution was added to the reaction mixture under
cooling to make it alkaline. After removing solid material, the
filtrate was condensed under reduced pressure and the obtained
residue was applied to silica gel column chromatography to obtain
6.08 g of the title compound as yellowish white powder.
m.p. 225.degree. to 227.degree. C.
Mass (CI); m/z=379 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.12 to 1.33 (2H, m), 1.72 to 1.92 (2H,
m), 2.04 to 2.35 (3H, m), 2.09 (3H, s), 2.52 to 2.68 (1H, m), 2.68
to 2.93 (4H, m), 2.93 to 3.18 (3H, m), 3.94 to 4.12 (1H, m), 4.55
to 4.70 (1H, m), 6.65 (1H, s, br), 7.79 (2H, d, J=8.8 Hz), 7.89
(2H, d, J=8.8 Hz), 8.65 (1H, s) (2) N-
(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]ani
line.multidot.2HCl salt
50 ml of conc. hydrochloric acid was added to 6.08 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-acetylpiperidin-4-yl)
acetyl]aniline, and after refluxing the mixture under heating, the
solvent was removed by distillation under reduced pressure. The
obtained solid was washed with hot-ethanol to obtain 5.13 g of the
title compound as yellowish white powder.
Mass (CI); m/z=337 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.48 to 1.69 (2H, m), 1.84
to 2.00 (2H, m), 2.10 to 2.35 (3H, m), 2.72 to 3.21 (8H, m), 3.21
to 3.38 (2H, m), 7.92 (2H, d, J=9.2 Hz), 7.99 (2H, d, J=8.6 Hz),
8.84 (1H, s), 10.64 (1H, s)
(3)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperidin-4-yl)
acetyl]aniline
50 ml of acetone, 1.14 g of potassium carbonate and 0.4 ml of
benzyl bromide were added to 1.34 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]a
niline, and the mixture was stirred at room temperature for 4
hours. After separating the solid by filtration and removing the
solvent by distillation under reduced pressure, the obtained
residue was applied to silica gel column chromatography to obtain
1.05 g of the title compound as yellowish white powder.
m.p. 212.degree. to 214.degree. C. (decomposed)
Mass; m/z=426 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.28 to 1.48 (2H, m), 1.67 to 1.80 (2H,
m), 1.90 to 2.09 (3H, m), 2.12 to 2.28 (2H, m), 2.79 to 2.90 (6H,
m), 2.98 to 3.05 (2H, m), 3.49 (2H, s), 6.42 (1H, s), 7.20 to 7.38
(5H, m), 7.77 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 8.66 (1H,
s)
EXAMPLE 27
N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}ani
line (Compound II-219 in Table 1)
In the same manner as in Example 26-(1), (2) and (3) except for
using 4-chloro-5-methylpyrimidine in place of
4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine and using
2-chloromethylpyridine in place of benzyl bromide in Example
26-(1), (2) and (3), the following compounds were obtained,
respectively.
(1)
N-(5-methylpyrimidin-4-yl)-4-[(1-acetylpiperidin-4yl)acetyl]aniline
Yellowish white solid
Mass (CI); m/z=353 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.12 to 1.30 (2H, m), 1.73 to 1.93 (3H,
m), 2.08 (3H, s), 2.26 (3H, s), 2.52 to 2.67 (1H, m), 2.84 to 2.93
(2H, m), 3.02 to 3.17 (1H, m), 3.73 to 3.86 (1H, m), 4.54 to 4.67
(1H, m), 6.92 (1H, s), 7.82 (2H, d, J=8.6 Hz), 7.97 (2H, d, J=9.2
Hz), 8.24 (1H, s), 8.69 (1H, s)
(2) N-
(5-methylpyrimidin-4-yl)-4-[(piperidin-4-yl)acetyl]aniline
Yellowish white solid
Mass (CI); m/z=311 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.46 to 1.70 (2H, m), 1.82 to 1.98 (3H,
m), 2.42 (3H, s), 2.83 to 3.09 (2H, m), 3.02 (2H, d, J=6.7 Hz),
3.21 to 3.38 (2H, m), 7.85 (2H, d, J=8.5 Hz), 8.02 (2H, d, J=8.5
Hz), 8.43 (1H, s), 8.86 (1H, s), 10.36 (1H, s)
(3)
N-(5-methylpyrimidin-4-yl)-4-{[1-(2-pyridylmethyl)piperidin-4-yl]acetyl}an
iline
White crystal
m.p. 207.degree. to 209.degree. C.
Mass (CI); m/z=402 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.33 to 1.50 (2H, m), 1.66 to 1.81 (2H,
m), 1.81 to 1.94 (1H, m), 2.07 to 2.20 (2H, m), 2.52 (3H, s), 2.86
(2H, d, J=6.7 Hz), 2.78 to 2.95 (2H, m), 3.64 (2H, s), 6.63 (1H,
s), 7.11 to 7.20 (1H, m), 7.40 (1H, d, J=7.3 Hz), 7.61 to 7.70 (1H,
m), 7.79 (2H, d, J=8.5 Hz), 7.98 (2H, d, J=9.2 Hz), 8.25 (1H, s),
8.55 (1H, d, J=4.8 Hz), 8.70 (1H, s)
EXAMPLE 28
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-
4-yl)-2-butenoyl]aniline (Compound II-6 in Table 1)
30 ml of ethanol and 0.58 g of
4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.21
g of
4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline.multidot.trifluoro
acetate, 1 ml of an ethanol solution of hydrochloric acid
(containing 0.29 g of hydrochloric acid) was added thereto and the
mixture was stirred under heating at 60.degree. C. for 40 minutes.
Then, a saturated sodium hydrogen carbonate aqueous solution was
added thereto and the mixture was extracted with chloroform. After
drying over anhydrous sodium sulfate, the solvent was removed by
distillation under reduced pressure and the obtained residue was
applied to silica gel column chromatography to obtain 0.40 g of the
title compound as yellow powder.
m.p. 184.degree. to 185.degree. C.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.24 to 1.60 (3H, m), 1.60 to 1.82 (2H,
m), 1.88 to 2.05 (2H, m), 2.10 to 2.34 (4H, m), 2.80 to 2.98 (4H,
m), 2.98 to 3.08 (2H, m), 3.50 (2H, s), 6.48 (1H, s, br), 6.90 (1H,
d, J=16.9 Hz), 6.98 to 7.12 (1H, m), 7.12 to 7.41 (5H, m), 7.78
(2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.66 (1H, s)
EXAMPLE 29
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl
)butanoyl]aniline (Compound II-3 in Table 1)
30 ml of ethanol and 0.1 g of platinum oxide were added to 0.24 g
of
(E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin
-4-yl)-2-butenoyl]aniline, and the mixture was stirred at room
temperature under a hydrogen stream for 45 minutes. After removing
the solid by filtration, the solvent was removed by distillation
and the obtained residue was applied to silica gel column
chromatography to obtain 0.19 g of the title compound as white
powder.
m.p. 170.degree. to 173.degree. C.
Mass (CI); m/z=455 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.14 to 1.38 (5H, m), 1.56 to 1.83 (6H,
m), 1.83 to 2.01 (2H, m), 2.14 to 2.27 (2H, m), 2.85 to 2.96 (4H,
m), 2.96 to 3.06 (2H, m), 3.49 (2H, s), 6.42 (1H, s, br), 7.19 to
7.35 (5H, m), 7.76 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.65
(1H, s)
EXAMPLE 30
(a)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-hydroxypiperi
din-4-yl)acetyl]aniline (Compound II-216 in Table 1),
(b)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-4-ethoxypiperid
in-4-yl)acetyl]aniline (Compound II-215 in Table 1) and
(c)
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4[(1-benzyl-1,2,5,6-tetrahy
dropyridin-4-yl)acetyl]aniline (Compound II-217 in Table 1)
30 ml of ethanol and 0.59 g of
4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine were added to 1.04
g of
4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.multidot.trifluoroacet
ate, then 1 ml of an ethanol solution of hydrochloric acid
(containing 0.29 g of hydrochloric acid) was added to the mixture
and the mixture was stirred at 60.degree. C. for 45 minutes.
Thereafter, 1 ml of triethylamine and water were added thereto, and
the reaction mixture was extracted with chloroform and dried over
anhydrous sodium sulfate. After removing the solvent by
distillation under reduced pressure, the obtained residue was
applied to silica gel column chromatography to obtain 0.60 g, 0.23
g and 0.05 g of the title compounds (a), (b) and (c),
respectively.
Compound of (a)
Yellowish white crystal
m.p. 193.degree. to 195.degree. C.
Mass (CI); m/z=443 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.62 to 1.88 (4H, m), 2.12 to 2.30 (2H,
m), 2.42 to 2.58 (2H, m), 2.58 to 2.72 (2H, m), 2.86 (2H, t, J=7.3
Hz), 2.93 to 3.06 (2H, m), 3.08 (2H, s), 3.56 (2H, s), 4.14 (2H,
s), 6.49 (1H, s, br), 7.21 to 7.38 (5H, m), 7.79 (2H, d, J=8.6 Hz),
7.95 (2H, d, J=8.6 Hz), 8.66 (1H, s)
Compound of (b)
Yellowish white crystal
m.p. 142.degree. to 143.degree. C.
Mass (CI); m/z=471 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.13 (3H, t, J=7.7 Hz), 1.74 to 1.95
(4H, m), 2.13 to 2.28 (2H, m), 2.28 to 2.44 (2H, m), 2.54 to 2.70
(2H, m), 2.85 (2H, t, J=7.3 Hz), 3.01 (2H, t, J=7.9 Hz), 3.10 (2H,
s), 3.40 to 3.48 (2H, m), 3.51 (2H, s, br), 6.43 (1H, s), 7.18 to
7.38 (5H, m), 7.76 (2H, d, J=8.5 Hz), 7.96 (2H, d, J=9.2 Hz), 8.65
(1H, s)
Compound of (c)
Pale yellow crystal
m.p. 165.degree. to 167.degree. C.
Mass; 424 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.12 to 2.28 (4H, m), 2.53 to 2.66 (2H,
m), 2.78 to 2.91 (2H, m), 2.91 to 3.08 (4H, m), 3.60 (2H, s), 3.61
(2H, s), 5.54 (1H, s, br), 6.47 (1H, s), 7.20 to 7.59 (5H, m), 7.77
(2H, d, J=8.5 Hz), 7.99 (2H, d, J=8.5 Hz), 8.65 (1H, s)
EXAMPLE 31
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzyl-4-piperidinylid
en)acetyl]aniline (Compound II-4 in Table 1)
To a mixed solvent of 40 ml of chloroform and 20 ml of ethanol were
added 2.33 g of 4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and
1.63 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and
further 6 ml of an ethanol solution of hydrochloric acid
(containing 0.4 g of hydrochloric acid) was added to the mixture
and the mixture was stirred at 50.degree. to 60.degree. C. for 3.5
hours under heating. Then, under ice cooling, a 28% sodium
methylate-methanol solution was added to the mixture to make it
alkaline, and then the solvent was removed by distillation under
reduced pressure and the obtained residue was applied to silica gel
column chromatography to obtain 0.3 g of the title compound as
yellowish white powder.
Mass (CI); m/z=425 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 2.13 to 2.24 (2H, m), 2.40 to 2.51 (2H,
m), 2.51 to 2.65 (4H, m), 2.75 to 2.90 (2H, m), 2.90 to 3.06 (4H,
m), 3.54 (2H, s), 6.50 (1H, s), 6.64 (1H, s), 7.18 to 7.43 (5H, m),
7.61 (2H, d, J=9.2 Hz), 7.95 (2H, d, J=8.5 Hz), 8.65 (1H, s)
EXAMPLE 32
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)pip
eridin-4-yl]propanoyl}aniline.multidot.2HCl
(2HCl salt of Compound II-104 in Table 1)
30 ml of 1,2-dichloroethane and 0.07 ml of triethylsilane were
added to 0.20 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-thienylmethyl)pi
peridin-4-yl]propenoyl}aniline, then 0.35 ml of trifluoroacetic
acid was added to the mixture and the mixture was stirred at
50.degree. C. for 3 hours under heating. After the reaction, the
solvent was removed by distillation under reduced pressure, a 1N
sodium hydroxide aqueous solution was added to the residue and the
residue was extracted with chloroform. After drying over anhydrous
sodium sulfate, the solvent was removed by distillation under
reduced pressure and the obtained residue was applied to silica gel
column chromatography to obtain an ocherous solid. The solid was
recrystallized form isopropyl alcohol and further treated with
hydrochloric acid to obtain 0.05 g of the title compound as white
powder.
(as 3/4H.sub.2 O adduct)
m.p. 187.degree. C. (decomposed)
Mass (CI); m/z=447 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.14 to 1.46 (2H, m), 1.46 to 1.84 (5H,
m), 1.88 to 2.12 (2H, m), 2.12 to 2.20 (2H, m), 2.74 to 3.10 (8H,
m), 3.70 to 3.85 (2H, m), 6.40 (1H, s), 6.87 to 7.02 (2H, m), 7.16
to 7.20 (6H, m), 7.76 (2H, d, J=9.2 Hz), 7.97 (2H, d, J=8.5 Hz),
8.65 (1H, s)
EXAMPLE 33
N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[3-(1-benzylpipe
ridin-4-yl)propanoyl]aniline (Compound II-167 in Table 1)
To 15 ml of ethanol were added 0.60 g of
4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.51 g of
7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, then 3
ml of an ethanol solution of hydrochloric acid (containing 0.19 g
of hydrochloric acid) was added to the mixture and the mixture was
reacted under reflux for 30 minutes. After cooling, a 28% sodium
methylate-methanol solution was added to the reaction mixture to
make it alkaline, and the mixture was condensed under reduced
pressure. The obtained residue was applied to silica gel column
chromatography to obtain 0.49 g of the title compound as white
crystal.
m.p. 189.degree. to 190.degree. C.
Mass; m/z=456 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.21 to 1.45 (3H, m), 1.56
to 1.81 (4H, m), 1.86 to 2.11 (3H, m), 2.47 to 3.08 (7H, m), 3.50
(2H, s), 4.83 (1H, br), 5.05 to 5.17 (1H, m), 7.16 to 7.38 (5H, m),
7.87 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.16 (1H, s), 8.68
(1H, s)
EXAMPLE 34
N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperi
din-4-yl)acetyl]aniline (Compound II-236 in Table 1)
In the same manner as in Example 33 except for using
4-[1-benzylpiperidin-4-yl)acetyl]aniline in place of
4-[3(1-benzylpiperidin-4-yl)propanoyl]aniline, the reaction was
carried out to obtain the tile compound as white crystal.
m.p. 174.degree. to 176.degree. C.
Mass; m/z=442 (M.sup.+)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.18 to 1.48 (3H, m), 1.66
to 1.80 (2H, m), 1.88 to 2.13 (4H, m), 2.50 to 2.66 (1H, m), 2.66
to 3.05 (3H, m), 2.85 (2H, d, J=6.7 Hz), 3.49 (2H, s), 5.09 to 5.20
(1H, m), 7.18 to 7.43 (6H, m), 7.85 (2H, d, J=9.2 Hz), 7.95 (2H, d,
J=9.2 Hz), 8.69 (1H, s)
EXAMPLE 35
N-(7-acetoxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiperi
din-4-yl)acetyl]aniline (Compound II-237 in Table 1)
20 ml of chloroform and 0.65 ml of acetic anhydride were added to
0.35 g of
N-(7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[(1-benzylpiper
idin-4-yl)acetyl]aniline, and the mixture was refluxed under
heating for 4 hours. Then, the solvent was removed by distillation
under reduced pressure and the obtained residue was applied to
silica gel column chromatography to obtain 0.16 g of the title
compound as white crystal.
(as 1/2H.sub.2 O adduct)
m.p. 210.degree. to 212.degree. C.
Mass; m/z=484 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.29 to 1.47 (3H, m), 1.54 to 1.63 (2H,
m), 1.68 to 1.94 (4H, m), 2.15 (3H, s), 2.67 to 3.04 (4H, m), 2.86
(2H, d, J=6.7 Hz), 3.50 (2H, s, br), 6.07 to 6.14 (1H, m), 6.53
(1H, s), 7.19 to 7.34 (5H, m), 7.78 (2H, d, J=9.2 Hz), 7.98 (2H, d,
J=8.6 Hz), 8.78 (1H, s)
EXAMPLE 36
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-aminobenzyl)piper
idin-4-yl]propanoyl}aniline (Compound II-272 in Table 1)
To 0.59 g of N-
(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-3-[1-(2-nitrobenzyl)piperid
in-4-yl]propanoyl)aniline were added 20 ml of ethanol, 40 ml of
methanol, 5 ml of acetic acid and 0.05 g of platinum oxide, and the
mixture was stirred at room temperature under a hydrogen stream for
4 hours. Then, after the solid was removed by filtration and the
solvent was removed by distillation under reduced pressure, a
saturated sodium hydrogen carbonate aqueous solution was added to
the residue and the mixture was extracted with chloroform. The
solvent was removed by distillation under reduced pressure and the
obtained solid was recrystallized from ethanol to obtain 0.32 g of
the title compound as pale brown crystal.
Mass; m/z=455 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.12 to 1.32 (3H, m), 1.56 to 1.77 (4H,
m), 1.83 to 1.98 (2H, m), 2.14 to 2.28 (2H, m), 2.79 to 3.07 (8H,
m), 3.47 (2H, s), 4.81 (2H, s, br), 6.43 (1H, s, br), 6.62 to 6.68
(2H, m), 6.97 (1H, d, J=6.7 Hz), 7.05 to 7.11 (1H, m), 7.76 (2H, d,
J=8.5 Hz), 7.97 (2H, d, J=9.2 Hz), 8.65 (1H, s)
EXAMPLE 37
N-
(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-{3-[1-(2-acetylaminobenzyl)
piperidin-4-yl]propanoyl}aniline (Compound II-249 in Table 1)
To 0.17 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(2-aminobenzyl)pipe
ridin-4-yl]propanoyl)aniline were added 30 ml of chloroform, 1 ml
of acetic anhydride and 0.38 g of 4-dimethylaminopyridine, and the
mixture was stirred at 50.degree. C. for 10 minutes. Then, the
solvent was removed by distillation under reduced pressure and the
obtained residue was applied to silica gel column chromatography to
obtain 0.06 g of the title compound as white crystal.
m.p. 219.degree. to 221.5.degree. C.
Mass; m/z=497 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.14 to 1.34 (2H, m), 1.34 to 1.50 (1H,
m), 1.66 to 1.89 (4H, m), 1.96 to 2.10 (2H, m), 2.14 (3H, s), 2.11
to 2.28 (2H, m), 2.80 to 3.08 (8H, m), 3.57 (2H, s), 6.44 (1H, s),
6.94 to 7.01 (1H, m), 7.25 (2H, d, J=6.1 Hz), 7.23 to 7.31 (1H, m),
7.78 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=9.2 Hz), 8.27 (1H, d, J=8.6
Hz), 8.65 (1H, s), 11.04 (1H, s)
EXAMPLE 38
N-acetyl-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4yl)-4-[3-(1-benzylpiperi
din-4-yl)propanoyl]aniline.multidot.2HCl (2HCl salt of Compound
II-221 in Table 1)
To 10 ml of a chloroform solution containing 0.72 g of
N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4
-yl)-4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline were added
under ice cooling 0.66 g of triethylamine and 0.46 ml of acetyl
chloride. After stirring under ice cooling for one hour, a
saturated saline solution was added to the mixture and the mixture
was extracted with chloroform. The chloroform layer was dried over
anhydrous sodium sulfate and condensed under reduced pressure. The
obtained residue was applied to silica gel column chromatography to
obtain the free material of the title compound. This material was
dissolved in ethyl acetate and treated with a hydrogen chloride gas
to obtain 0.54 g of the title compound as pale brown crystal.
(as H.sub.2 O adduct)
m.p. 128.degree. to 131.5.degree. C.
Mass (CI); m/z=483 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 to 1.96 (5H, m), 2.00 to 2.38 (4H,
m), 2.23 (3H, s), 2.53 to 2.86 (4H, m), 2.93 to 3.12 (2H, m), 3.34
to 3.57 (4H, m), 4.16 (2H, d, J=4.4 Hz), 7.35 (2H, d, J=8.1 Hz),
7.40 to 7.53 (3H, m), 7.57 to 7.70 (2H, m), 8.08 (2H, d, J=8.1 Hz),
8.83 (1H, s), 12.25 (1H, s, br)
EXAMPLES 39 TO 78
In the same manner as in Example 1, 2, 3, 23, 24 or 36, the
following compounds were obtained.
______________________________________ Exam- Characteristics. ple
Compound Physical properties ______________________________________
39 N-(5,6-dihydro-7H-cyclopenta- (as 3/2H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(2- White powder
fluorobenzyl)piperidin-4-yl]- m.p. 205 to 209.degree. C.
propanoyl}aniline.2HCl (2HCl salt (decomposed) of Compound II-20 in
Table 1) 40 N-(5,6-dihydro-7H-cyclopenta- White powder
[d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 213 to 216.degree. C.
chlorobenzyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 50 in
Table 1) 41 N-(5,6-dihydro-7H-cyclopenta- (as 1/4H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(3- Yellow crystal
chlorobenzyl)piperidin-4-yl]- m.p. 189 to 191.degree. C.
propanoyl}aniline.2HCl (2Hcl salt of Compound II-56 in Table 1) 42
N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(3- Yellowish white
methoxybenzyl)piperidin-4-yl]- powder propanoyl}aniline.2HCl (2HCl
salt m.p. 186 to 188.degree. C. of Compound II-32 in Table 1) 43
N-(5,6-dihydro-7H-cyclopenta- Yellowish white
[d]pyrimidin-4-yl)-4-{3-[1-(2- powder
methoxybenzyl)piperidin-4-yl]- m.p. 169.5 to 172 propanoyl}aniline
(Compound II- .degree.C. 38 in Table 1) 44
N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(3- Yellowish white
benzyloxybenzyl)piperidin-4- powder yl]propanoyl}aniline (Compound
m.p. 193 to 195.degree. C. II-239 in Table 1) 45
N-(5,6-dihydro-7H-cyclopenta- Yellowish white
[d]pyrimidin-4-yl)-4-{3-[1-(4- powder methylbenzyl)piperidin-4-yl]-
m.p. 192 to 195.degree. C. propanoyl}aniline.HCl (HCl salt
(decomposed) of Compound II-68 in Table 1) 46
N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(3- White powder
methylbenzyl)piperidin-4-yl]- m.p. 116 to 117.5 propanoyl}aniline
(Compound II- .degree.C. 214 in Table 1) 47
N-(5,6-dihydro-7H-cyclopenta- (as 1/4H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-{3-[1-(4- Yellowish white
trifluoromethylbenzyl)piperi- crystal din-4-yl]propanoyl}aniline
m.p. 216 to 218.degree. C. (Compound II-80 in Table 1) 48
N-(5,6-dihydro-7H-cyclopenta- Yellow crystal
[d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 209 to 211.5
trifluoromethylbenzyl)piperi- .degree.C. din-4-yl]propanoyl}aniline
(Compound II-232 in Table 1) 49 N-(5,6-dihydro-7H-cyclopenta- White
powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 180 to 182.5
cyanobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound
II- 218 in Table 1) 50 N-(5,6-dihydro-7H-cyclopenta- White powder
[d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 188 to 190.degree. C.
cyanobenzyl)piperidin-4-yl]- (decomposed) propanoyl}aniline
(Compound II- 225 in Table 1) 51 N-(5,6-dihydro-7H-cyclopenta-
White powder [d]pyrimidin-4-yl)-4-{3-[1-(1- m.p. 197 to 199.degree.
C. naphthylmethyl)piperidin-4-yl]- propanoyl}aniline (Compound II-
224 in Table 1) 52 N-(5,6-dihydro-7H-cyclopenta- Pale yellow
crystal [d]pyrimidin-4-yl)-4-{3-[1- m.p. 190 to 193.degree. C.
(sec-phenethyl)piperidin-4-yl]- (decomposed) propanoyl}aniline
(Compound II- 86 in Table 1) 53 N-(5,6-dihydro-7H-cyclopenta-
Yellow crystal [d]pyrimidin-4-yl)-4-{3-[1-(2- m.p. 181.5 to 183
pyridylmethyl)piperidin-4-yl]- .degree.C. propanoyl}aniline
(Compound II- 110 in Table 1) 54 N-(5,6-dihydro-7H-cyclopenta- Pale
brown crystal [d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 167 to
169.degree. C. pyridylmethyl)piperidin-4-yl]- propanoyl}aniline
(Compound II- 210 in Table 1) 55 N-(5,6-dihydro-7H-cyclopenta- (as
1/4H.sub.2 O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(4- Pale brown
crystal pyridylmethyl)piperidin-4-yl]- m.p. 174 to 175.degree. C.
propanoyl}aniline (Compound II- 116 in Table 1) 56
N-(5,6-dihydro-7H-cyclopenta- Pale yellow crystal
[d]pyrimidin-4-yl)-4-{3-[1-(6- m.p. 200 to 201.5
methyl-2-pyridylmethyl)piperi- .degree.C.
din-4-yl]propanoyl}aniline (Compound II-238 in Table 1) 57
(E)-N-(5,6-dihydro-7H-cyclo- Yellowish white
penta[d]pyrimidin-4-yl)-4-{3- crystal
[1-(2-thienylmethyl)piperidin- m.p. 199 to 200.degree. C.
4-yl]propenoyl]aniline (Compound II-107 in Table 1) 58
N-(5,6-dihydro-7H-cyclopenta- White crystal
[d]pyrimidin-4-yl)-4-{3-[1-(3, m.p. 198.5 to 200
4-methylenedioxybenzyl)piperi- .degree.C.
din-4-yl]propanoyl}aniline (Compound II-231 in Table 1) 59
N-(5,6-dihydro-7H-cyclopenta- Yellowish white
[d]pyrimidin-4-yl)-4-{3-[1-(3, crystal
4-ethylenedioxybenzyl)piperi- m.p. 185 to 186.degree. C.
din-4-yl]propanoyl}aniline (Compound II-235 in Table 1) 60
N-(5,6-dihydro-7H-cyclopenta- White crystal
[d]pyrimidin-4-yl)-4-{3-[1-(2, m.p. 179 to 181.degree. C.
3-dimethoxybenzyl)piperidin-4- yl]propanoyl}aniline (Compound
II-233 in Table 1) 61 N-(6,6-dimethyl-5,6-dihydro-7H- (as
1/2H.sub.2 O adduct) cyclopenta[d]pyrimidin-4-yl)-4- Pale yellow
crystal [3-benzylpiperidin-4-yl)- m.p. 225 to 227.degree. C.
propanoyl]aniline.2HCl (2HCl salt of Compound II-198 in Table 1) 62
N-(pyrimidin-4-yl)-4-[3-(1-ben- Pale yellow crystal
zylpiperidin-4-yl)propanoyl]- m.p. 149.5 to 151 aniline (Compound
II-136 in .degree.C. Table 1) 63 N-(5-methylpyrimidin-4-yl)-4-
(1/2H.sub.2 O adduct) [3-(1-benzylpiperidin-4-yl)- White powder
propanoyl]aniline.2HCl (2HCl salt m.p. 180 to 184.degree. C. of
Compound II-189 in Table 1) 64 N-(5,6-diethylpyrimidin-4-yl)- White
needle crystal 4-[3-(1-benzylpiperidin-4-yl)- m.p. 137 to
139.degree. C. propanoyl]aniline (Compound II- 223 in Table 1) 65
N-(5-butyl-6-methylpyrimidin-4- White powder
yl)-4-[3-(1-benzylpiperidin-4- m.p. 149.5 to 151
yl)propanoyl]aniline (Compound .degree.C. II-154 in Table 1) 66
N-(5-ethoxycarbonylpyrimidin-4- Pale yellow crystal
yl)-4-[3-(1-benzylpiperidin-4- m.p. 117 to 118.5
yl)propanoyl]aniline (Compound .degree.C. II-222 in Table 1) 67
N-(6-ethoxypyrimidin-4-yl)-4- Pale yellow crystal
[3-(1-benzylpiperidin-4-yl)- m.p. 168 to 170.degree. C.
propanoyl]aniline (Compound II- 149 in Table 1) 68
N-(6-chloro-5-methylpyrimidin- (as 1/2H.sub.2 O adduct)
4-yl)-4-[3-(1-benzylpiperidin- White needle crystal
4-yl)propanoyl]aniline m.p. 175 to 177.degree. C. (Compound II-190
in Table 1) 69 N-(5-chloropyrimidin-4-yl)-4- Pale brown crystal
[3-(1-benzylpiperidin-4-yl)- m.p. 142 to 144.degree. C.
propanoyl]aniline (Compound II- 229 in Table 1) 70
N-(5-bromopyrimidin-4-yl)-4-[3- Pale yellow crystal
(1-benzylpiperidin-4-yl)propan- m.p. 151 to 153.degree. C.
oyl]aniline (Compound II-230 in Table 1) 71
N-(5-nitro-6-methoxypyrimidin-
Yellow crystal 4-yl)-4-[3-(1-benzylpiperidin- m.p. 126 to
128.degree. C. 4-yl)propanoyl]aniline (Compound II-240 in Table 1)
72 N-(5-methylpyrimidin-4-yl)-4- White crystal
{3-[1-(2-pyridylmethyl)piperi- m.p. 142 to 143.degree. C.
din-4-yl)propanoyl]aniline (Compound II-248 in Table 1) 73
N-(5-amino-6-chloropyrimidin-4- (as 1/4H.sub.2 O adduct)
yl)-4-[3-(1-benzylpiperidin-4- Yellowish orange
yl)propanoyl]aniline (Compound crystal II-241 in Table 1) m.p. 163
to 165.degree. C. 74 N-(5,6-dihydro-7H-cyclopenta- White powder
[d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 200 to 202.degree. C.
nitrobenzyl)piperidin-4-yl]- propanoyl}aniline (Compound II- 74 in
Table 1) 75 N-(5,6-dihydro-7H-cyclopenta- White powder
[d]pyrimidin-4-yl)-4-{3-[1-(3- m.p. 184.5 to 186
nitrobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound
II- 243 in Table 1) 76 N-(5,6-dihydro-7H-cyclopenta- Pale brown
powder [d]pyrimidin-4-yl)-4-{3-[1-(4- m.p. 174 to 176.5
aminobenzyl)piperidin-4-yl]- .degree.C. propanoyl}aniline (Compound
II- 271 in Table 1) 77 N-(5,6-dihydro-7H-cyclopenta- (as 1/2H.sub.2
O adduct) [d]pyrimidin-4-yl)-4-{3-[1-(3- White needle crystal
aminobenzyl)piperidin-4-yl]- m.p. 187 to 188.degree. C.
propanoyl}aniline (Compound II- 244 in Table 1) 78
N-(5,6-dihydro-7H-cyclopenta- White powder
[d]pyrimidin-4-yl)-4-{3-[1-(4- NMR (.delta., CD.sub.3 OD);
hydroxybenzyl)piperidin-4-yl]- 1.20-1.49 (3H, m), propanoyl}aniline
(Compound II- 1.58-1.80 (4H, m), 44 in Table 1) 1.98-2.10 (2H, m),
2.15-2.27 (2H, m), 2.87-3.03 (8H, m), 3.59 (2H, s), 6.86 (2H, d,
J=8.4Hz), 7.29 (2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.8Hz), 7.98 (2H,
d, J=8.8Hz), 8.51 (1H, s)
______________________________________
EXAMPLES 79 TO 91
In the same manner as in Example 3, 25, 26, 27 or 31, the following
compounds were obtained.
______________________________________ Exam- Characteristics. ple
Compound Physical properties ______________________________________
79 N-(5,6-dimethylpyrimidin-4-yl- White crystal
4-[(1-benzylpiperidin-4-yl)- m.p. 212 to 214.degree. C.
acetyl]aniline (Compound II-234 in Table 1) 80
N-(5,6-dihydro-7H-cyclopenta- (as 3/2H.sub.2 O adduct)
[d]pyrimidin-4-yl)-4-[(1-benz- White crystal
ylpiperidin-4-yl)acetyl]-2- m.p. 228 to 232.degree. C.
methoxyaniline.2HCl (2HCl salt of Compound II-245 in Table 1) 81
N-(5,6,7,8-tetrahydroquinazo- (as H.sub.2 O adduct)
lin-4-yl)-4-[(1-benzylpiperi- White crystal
din-4-yl)acetyl]-2-methoxy- m.p. 215 to 219.degree. C. aniline.2HCl
(2HCl salt of Compound II-246 in Table 1) 82
N-(5,6-dihydro-7H-cyclopenta- Pale yellow crystal
[d]pyrimidin-4-yl)-4-[(1-benz- m.p. 128 to 130.degree. C.
ylpiperidin-4-yl)acetyl]-2- chloroaniline (Compound II-247 in Table
1) 83 N-(5,6-dihydro-7H-cyclopenta- Yellow crystal
[d]pyrimidin-4-yl)-4-{[1-(4- m.p. 195 to 197.degree. C.
fluorobenzyl)-4-piperidinyli- (decomposed) den]acetyl}aniline
(Compound II-10 in Table 1) 84 N-(5,6-dihydro-7H-cyclopenta- White
crystal [d]pyrimidin-4-yl)-4-{[1-(4- m.p. 191 to 193.degree. C.
fluorobenzyl)piperidin-4-yl]- acetyl}aniline (Compound II-7 in
Table 1) 85 N-(5,6-dihydro-7H-cyclopenta- White crystal
[d]pyrimidin-4-yl)-4-{[1-(2- m.p. 196 to 197.5
pyridylmethyl)piperidi-4-yl]- .degree.C. acetyl}aniline (Compound
II-109 in Table 1) 86 N-(5,6-dihydro-7H-cyclopenta- Yellowish white
[d]pyrimidin-4-yl)-4-{[1-(2- crystal methoxybenzyl)piperidin-4-yl]-
m.p. 168 to 170.degree. C. acetyl}aniline (Compound II-37 in Table
1) 87 N-(5,6-dihydro-7H-cyclopenta- White crystal
[d]pyrimidin-4-yl)-4-{[1-(2- m.p. 197 to 199.degree. C.
thienylmethyl)piperidin-4-yl]- acetyl}aniline (Compund II-103 in
Table 1) 88 N-(5-methylpyrimidin-4-yl)-4- White crystal
{[1-(2-thienylmethyl)piperidin- m.p. 209 to 211.degree. C.
4-yl]acetyl}aniline (Compound II-258 in Table 1) 89
N-(5-methylpyrimidin-4-yl)-4- White crystal
[(1-phenethylpiperidin-4-yl)- m.p. 193 to 194.degree. C.
acetyl]aniline (Compound II-301 in Table 1) 90
N-(5-methylpyrimidin-4-yl)-4- White crystal
[(1-diphenylmethylpiperidin-4- m.p. 195.5 to 197 yl)acetyl]aniline
(Compound II- .degree.C. 302 in Table 1) 91
N-(5,6-dihydro-7H-cyclopenta- White crystal
[d]pyrimidin-4-yl)-4-{[1-(2- m.p. 207 to 209.degree. C.
furylmethyl)piperidin-4-yl]- acetyl}aniline (Compund II-269 in
Table 1) 92 N-(5-methylpyrimidin-4-yl)-4- Yellowish white
{[1-(3-phenylpropyl)piperidin- crystal 4-yl]acetyl}aniline
(Compound m.p. 167.5 to 169 II-317 in Table 1) .degree.C. 93
N-(5-ethylpyrimidin-4-yl)-4- White crystal
[(1-benzylpiperidin-4-yl)- m.p. 169 to 171.degree. C.
acetyl]aniline (Compound II-252 in Table 1) 94
N-(5-propylpyrimidin-4-yl)-4- Yellow crystal
[(1-benzylpiperidin-4-yl)- m.p. 140.5 to 141.5 acetyl]aniline
(Compound II-253 .degree.C. in Table 1) 95
N-(5-methylpyrimidin-4-yl)-4- White crystal
{[1-(3-thienylmethyl)piperidin- m.p. 212 to 214.degree. C.
4-yl]acetyl}aniline (Compound II-259 in Table 1) 96
N-(5,6-dihydro-7H-cyclopenta- Yellowish white
[d]pyrimidin-4-yl)-4-{[1-(3- crystal thienylmethyl)piperidin-4-yl]-
m.p. 193 to 195.degree. C. acetyl}aniline (Compound II-267 in Table
1) 97 N-(5-methylpyrimidin-4-yl)-4- Pale brown crystal
[(1-benzylpiperidin-4-yl)- m.p. 168 to 170.degree. C.
acetyl]-3-methoxyaniline (Compound II-266 in Table 1)
______________________________________
Reference Example 1
4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene
Under ice cooling, 0.40 g of 64% sodium hydride was added to 3.03 g
of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 30 ml of
tetrahydrofuran. After about 10 minutes, 4.07 g of
4-formyl-1-benzylpiperidine was added to the mixture. The mixture
was stirred under ice cooling for 30 minutes and then stirred at
room temperature for about 16 hours. After completion of the
reaction, water was added to the reaction mixture, and the mixture
was extracted with ethyl acetate. The extract was dried over
anhydrous sodium sulfate, and the solvent was removed under reduced
pressure. The obtained residue was applied to silica gel column
chromatography to obtain 1.99 g of the title compound as pale
yellow crystal.
Mass; m/z=350 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.47 to 1.70 (2H, m), 1.70 to 1.87 (2H,
m), 1.97 to 2.16 (2H, m), 2.16 to 2.40 (1H, m), 2.86 to 3.02 (2H,
m), 3.53 (2H, m), 6.82 (1H, dd, J=15.6 Hz, J=-1 Hz), 7.09 (1H, dd,
J=15.6 Hz, J=6.4 Hz), 7.21 to 7.37 (5H, m), 8.03 (2H, d, J=8.8 Hz),
8.32 (2H, d, J=8.8 Hz)
Reference Example 2
(E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline
1.27 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene
was added to a mixed solution of 10 ml of acetic acid and 2 ml of
hydrochloric acid, and then 1.38 g of stannous chloride was added
thereto under ice cooling. The mixture was stirred for 24 hours.
During the reaction, 0.69 g of stannous chloride was further added
twice. After completion of the reaction, the reaction mixture was
condensed under reduced pressure to obtain 5.50 g of a crude
product of the title compound. This was used without purification
for the next reaction.
Mass; m/z=320 (M.sup.+)
TLC Rf value; 0.42 (silica gel produced by Merck Co.; 60F.sub.254,
solvent; chloroform/methanol=9/1)
Reference Example 3
4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene
0.28 g of lithium chloride, 0.85 g of diisopropylethylamine and
2.13 g of 4-formyl-l-t-butoxycarbonylpiperidine were added to 2.0 g
of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 20 ml of
acetonitrile, and the mixture was stirred at room temperature for
about 3 days. Then, water was added to the reaction mixture, and
the mixture was extracted with toluene. The extract was dried over
anhydrous sodium sulfate and condensed. The obtained residue was
applied to silica gel column chromatography to obtain 1.76 g of the
title compound as pale yellow crystal.
Mass (CI); m/z=261 (M.sup.+ -99)
NMR (.delta., CDCl.sub.3); 1.37 to 1.53 (2H, m), 1.47 (9H, s), 1.77
to 1.86 (2H, m), 2.40 to 2.52 (2H, m), 2.74 to 2.87 (2H, m), 4.08
to 4.28 (2H, m), 6.85 (1H, dd, J=1.5 Hz, 15.6 Hz), 7.06 (1H, dd,
J=6.4 Hz, 15.1 Hz), 8.05 (2H, d, J=8.8 Hz), 8.32 (2H, d, J=8.8
Hz)
Reference Example 4
(E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene
3 ml of trifluoroacetic acid was added to 2.52 g of
(E)-4-[3-(1-t-butoxycarbonylpiperidin-4-yl)propenoyl]nitrobenzene
dissolved in 20 ml of methylene chloride, and the mixture was
stirred at room temperature for 3 hours. Subsequently, 7 ml of
trifluoroacetic acid was further added to the mixture, and the
mixture was stirred for 3 hours. Then, the solvent was removed by
distillation, and a saturated sodium hydrogen carbonate solution
was added to the residue. After the mixture was extracted with
ethyl acetate, the extract was dried over anhydrous sodium sulfate
and condensed. The obtained solid was washed with methylene
chloride to obtain 0.7 g of the title compound as pale yellow
powder.
Mass (CI); m/z=261 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.80 to 2.12 (4H, m), 2.30
to 2.70 (1H, m), 2.89 to 3.08 (2H, m), 3.44 to 3.68 (2H, m), 6.90
(1H, d, J=15 to 16 Hz), 7.04 (1H, dd, J=15 to 16 Hz, J=6 to 7 Hz),
8.06 (2H, d, J=8 to 9 Hz), 8.32 (2H, d, J=8 to 9 Hz)
Reference Example 5
(E)-4-{3-[1-(3-fluorobenzyl)piperidin-4-yl]propenoyl}nitrobenzene
1.11 g of 3-fluorobenzylbromide and 2.53 g of potassium carbonate
were added to 3.0 g of
(E)-4-[3-(piperidin-4-yl)propenoyl]nitrobenzene dissolved in 30 ml
of dimethylformamide at room temperature, and the mixture was
stirred for 2 hours. After completion of the reaction, water was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The extract was dried over anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The obtained
residue was applied to silica gel column chromatography to obtain
1.06 g of the title compound as pale yellow crystal.
Mass (CI); m/z=369 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.46 to 1.88 (4H, m), 2.00 to 2.12 (2H,
m), 2.18 to 2.40 (1H, m), 2.84 to 3.50 (2H, m), 3.51 (2H, s), 6.82
(1H, dd, J=-1 Hz, 15.6 Hz), 6.88 to 6.99 (1H, m), 7.03 to 7.14 (3H,
m), 7.20 to 7.34 (1H, m), 8.04 (2H, d, J=8.8 Hz), 8.31 (2H, d,
J=8.8 Hz)
In the same manner as in Reference example 5, the following
compounds were obtained.
Reference Example 6
(E)-4-{3-[1-(4-fluorobenzyl)piperidin-4-yl]propenoyl}-nitrobenzene
Orange powder
Mass (CI); m/z=369 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.45 to 1.88 (4H, m), 1.92 to 2.16 (2H,
m), 2.16 to 2.40 (1H, m), 2.85 to 3.00 (2H, m), 3.47 (2H, s), 6.81
(1H, dd, J=-1 Hz, 15.6 Hz), 6.95 to 7.05 (2H, m), 7.07 (1H, dd,
J=6.4 Hz, J=15.6 Hz), 7.24 to 7.31 (2H, m), 8.03 (2H, d, J=8.8 Hz),
8.31 (2H, d, J=8.8 Hz)
Reference Example 7
(E)-4-(3-[1-(4-methoxybenzyl)piperidin-4-yl]propenoyl)nitrobenzene
Brown oily product
Mass; m/z=380 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.46 to 1.84 (4H, m), 1.97 to 2.10 (2H,
m), 2.20 to 2.35 (1H, m), 2.91 to 2.99 (2H, m), 3.46 (2H, s), 3.82
(3H, s), 6.88 to 6.92 (3H, m), 7.10 (1H, dd, J=6 to 7 Hz, 15 to 16
Hz), 7.22 to 7.35 (2H, m), 8.03 (2H, d, J=8 to 9 Hz), 8.32 (2H, d,
J=8 to 9 Hz)
Reference Example 8
(E)-4-(3-[1-(4-picolyl)piperidin-4-yl]propenoyl)nitrobenzene
Brown crystal
Mass; m/z=351 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.55 to 1.66 (2H, m), 1.78 to 1.85 (2H,
m), 1.85 to 2.14 (2H, m), 2.25 to 2.37 (1H, m), 2.87 to 2.97 (2H,
m), 3.53 (2H, s), 6.83 (1H, d, J=15.6 Hz), 7.08 (1H, dd, J=6.8 Hz,
J=15.6 Hz), 7.28 (2H, d, J=5.9 Hz), 8.05 (2H, d, J=8.8 Hz), 8.32
(2H, d, J=8.8 Hz), 8.55 (2H, d, J=5.9 Hz)
Reference Example 9
4-chloro-7-fluoro-5,6-dihydro-7H-cyclopenta[d]pyrimidine
(1) 5.54 g of lithium hydroxide.multidot.hydrate was added to 24.2
g of 7-acetoxy-4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine
dissolved in 150 ml of tetrahydrofuran, and the mixture was stirred
at room temperature for about 20 hours. After the reaction, water
was added to the reaction mixture, and then the mixture was
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate and then condensed. The obtained residue was applied
to silica gel column chromatography to obtain 10.5 g of
4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine.
Mass; m/z=170
NMR (.delta., CDCl.sub.3); 2.00 to 2.23 (1H, m), 2.52 to 2.73 (1H,
m), 2.79 to 3.02 (1H, m), 3.02 to 3.24 (1H, m), 5.20 (1H, br), 5.30
(1H, t, J=8.0 Hz), 8.90 (1H, s)
(2) Under ice cooling, 3.9 ml of diethylaminosulfite trifluoride
(DAST) was added dropwise to 5.00 g of
4-chloro-7-hydroxy-5,6-dihydro-7H-cyclopenta[d]pyrimidine obtained
above dissolved in 40 ml of chloroform, and the mixture was stirred
at the same temperature for 10 minutes. After the solvent was
removed under reduced pressure, water was added to the mixture, and
the mixture was extracted with ethyl acetate. The extract was dried
over anhydrous sodium sulfate and condensed. The obtained residue
was applied to silica gel column chromatography to obtain 3.09 g of
the title compound as a yellow oily product.
Mass; m/z=172 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.23 to 2.77 (2H, m), 2.87 to 3.40 (2H,
m), 5.78 to 5.89 and 6.05 to 6.18 (total 1H, each m), 9.01 (1H,
s)
Reference Example 10
4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline
2.00 g of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]nitrobenzene
was added to a mixed solvent of 30 ml of ethanol and 5 ml of acetic
acid, and then 0.20 g of platinum oxide was added thereto.
Thereafter, the mixture was stirred in a hydrogen stream at room
temperature for 7.5 hours. After the reaction, the catalyst was
removed by filtration, and the filtrate was condensed under reduced
pressure. The obtained residue was applied to silica gel column
chromatography to obtain 0.69 g of the title compound as pale
yellow crystal.
Mass; m/z=322 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.32 to 1.54 (3H, m), 1.63 to 1.78 (4H,
m), 2.14 to 2.25 (2H, m), 2.86 (2H, t, J=7.3 Hz), 3.09 to 3.18 (2H,
m), 3.77 (2H, s), 6.63 (2H, d, J=8.8 Hz), 7.28 to 7.37 (5H, m),
7.78 (2H, d, J=8.8 Hz)
Reference Example 11
(E)-4-[3-(1-acetylpiperidin-4-yl) propenoyl]nitrobenzene
In the same manner as in Reference example 3 except for using
4-formyl-l-acetylpiperidine in place of
4-formyl-t-butoxycarbonylpiperidine, the reaction was carried out
to obtain the title compound as yellowish orange solid.
Mass; m/z=302 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.36 to 1.57 (2H, m), 1.83 to 1.99 (2H,
m), 2.12 (3H, s), 2.48 to 2.75 (2H, m), 3.10 to 3.25 (1H, m), 3.85
to 3.96 (1H, m), 4.63 to 4.75 (1H, m), 6.86 (1H, d, J=15.9 Hz),
7.06 (1H, dd, J=15.8 Hz, 6.7 Hz), 8.06 (2H, d, J=9.2 Hz), 8.32 (2H,
d, J=9.2 Hz)
Reference Example 12
4-[3-(1-acetylpiperidin-4-yl) propanoyl]aniline
To 6.74 g of
(E)-4-[3-(1-acetylpiperidin-4-yl)propenoyl]nitrobenzene were added
300 ml of methanol and 0.30 g of platinum oxide, and under a
hydrogen stream, the mixture was stirred at room temperature for 3
hours. Then, the solid was removed by filtration, the solvent was
removed by distillation under reduced pressure, and the obtained
residue was applied to silica gel column chromatography to obtain
4.81 g of the title compound as brownish white powder.
Mass; m/z=274 (M.sup.+)
NMR (.delta., CDCl.sub.3); 1.02 to 1.25 (2H, m), 1.46 to 1.86 (5H,
m), 2.08 (3H, s), 2.43 to 2.61 (1H, m), 2.90 (2H, t, J=7.3 Hz),
2.95 to 3.09 (1H, m), 3.70 to 3.86 (1H, m), 4.27(2H, s, br), 4.52
to 4.64 (1H, m), 6.65 (2H, d, J=8.6 Hz), 7.80 (2H, d, J=8.6 Hz)
Reference Example 13
N-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline
A mixed solution comprising 140 ml of a tetrahydrofuran solution
containing 10.00 g of 4-acetylaminoacetophenone and 10 ml of
hexamethylphosphoric acid triamide (HMPA) was cooled to -60.degree.
C. under an argon stream, and then 83 ml of a tetrahydrofuran
solution containing 1.5M of lithium diisopropylamide was added
dropwise to the mixture. After completion of the dropwise addition,
the mixture was stirred at -35.degree. to -30.degree. C. for 20
minutes and cooled again to -60.degree. C. To the mixture was added
dropwise 10.68 g of 1-benzyl-4-piperidone, and the temperature of
the resulting mixture was gradually raised to room temperature. The
reaction mixture was quenched to a saturated ammonium chloride
aqueous solution, and 3.62 g of the precipitated title compound was
collected by filtration. The filtrate was further extracted with
ethyl acetate and condensed, and then the condensate was applied to
silica gel column chromatography to obtain 8.28 g of the title
compound.
White crystal
Mass (CI); m/z=349 (M.sup.+ +1-H.sub.2 O)
NMR (.delta., CDCl.sub.3); 1.67 to 1.89 (4H, m), 2.22 (3H, s), 2.50
to 2.77 (4H, m), 3.05 (2H, s), 3.62 (2H, s), 4.14 (1H, s), 7.21 to
7.45 (5H, m), 7.66 (2H, d, J=9.2 Hz), 7.87 (2H, d, J=9.2 Hz), 8.07
(1H, s, br)
Reference Example 14
N-acetyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline and
N-acetyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline
To a chloroform solution containing 11.90 g of
N-acetyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline was
added 15 ml of pyridine under ice cooling, and then 3.8 ml of
thionyl chloride was added dropwise thereto. After completion of
the dropwise addition, the mixture was stirred at room temperature
for about 6 hours. After completion of the reaction, ice-water was
added and then a 1N sodium hydroxide aqueous solution was added to
the mixture to make it weak alkaline, then the mixture was
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate and then condensed. The residue obtained was applied
to silica gel column chromatography to obtain 7.11 g of the mixture
of the title compounds.
Brown liquid
Mass (CI); m/z=349 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 2.20 (3H, s), 2.37 to 2.63, 2.85 to 3.02
and 3.60 (total 8H, each m), 3.53 and 3.56 (total 2H, each s), 5.52
and 6.62 (total 1H, m and s, respectively), 7.18 to 7.39 (5H, m),
7.62 (2H, d, J=8.6 Hz), 7.85 to 8.05 (3H, m)
Reference Example 15
N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline
In a mixed solution of 80 ml of ethanol and 30 ml of toluene was
dissolved 7.10 g of the mixture of
N-acetyl-4[(1-benzyl-4-piperidinyliden)acetyl]aniline and
N-acetyl-4[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]aniline
obtained in Reference example 14, and then 0.10 g of platinum oxide
was added thereto. The mixture was stirred under a hydrogen stream
for 5.5 hours. After the reaction, the catalyst was removed by
filtration and condensed under reduced pressure. The residue
obtained was applied to silica gel column chromatography to obtain
5.54 g of the title compound.
Pale yellow crystal
Mass (CI); m/z=351 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.25 to 1.44 (2H, m), 1.63 to 1.77 (2H,
m), 1.88 to 2.07 (3H, m), 2.19 (3H, s), 2.76 to 2.92 (4H, m), 3.48
(2H, s), 7.18 to 7.38 (5H, m), 7.62 (2H, d, J=9.2 Hz), 7.89 (2H, d,
J=9.2 Hz), 8.13 (1H, s, br)
Reference example 16
4-[(1-benzylpiperidin-4-yl)acetyl]aniline.multidot.2HCl salt
5.54 g of N-acetyl-4-[(1-benzylpiperidin-4-yl)acetyl]aniline was
added to a mixed solution of 15 ml of ethanol and 20 ml of conc.
hydrochloric acid, and then the mixture was heated under reflux for
4.5 hours. After the reaction, the reaction mixture was condensed
under reduced pressure, and the obtained solid was washed with
ethanol to obtain 6.20 g of the title compound.
Pale brown crystal
Mass (CI); m/z=309 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3 -DMSO-d.sub.6); 1.68 to 1.97 (4H, m), 2.07
to 2.28 (1H, m), 2.82 to 3.10 (4H, m), 3.29 to 3.43 (2H, m), 4.27
(2H, d, J=5.5 Hz), 7.18 (2H, d, J=8.7 Hz), 7.31 to 7.51 (3H, m),
7.58 to 7.76 (2H, m), 7.87 (2H, d, J=8.7 Hz)
Reference Example 17
N-t-butoxycarbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline
30 ml of tetrahydrofuran was added to 2.00 g of
N-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyl
lithium.multidot.pentane solution was added thereto under an argon
stream at -78.degree. C. Then, 1.41 g of 1-benzyl-4-piperidone was
dissolved in 20 ml of tetrahydrofuran, and the solution was added
dropwise. After stirring for 2 hours, a saturated ammonium chloride
aqueous solution was added to the reaction mixture, and the mixture
was extracted with ethyl acetate and dried over anhydrous sodium
sulfate. The solvent was removed by distillation under reduced
pressure, and the obtained residue was applied to silica gel column
chromatography to obtain 2.07 g of the title compound as white
powder.
Mass (CI); m/z=307 (M.sup.+ -118)
NMR (.delta., CDCl.sub.3); 1.53 (9H, s), 1.60 to 1.75 (2H, m), 1.75
to 1.83 (2H, m), 2.43 to 2.53 (2H, m), 2.56 to 2.65 (2H, m), 3.06
(2H, s), 3.54 (2H, s), 4.10 (1H, s, br), 6.74 (1H, s, br), 7.23 to
7.35 (5H, m), 7.45 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=8.8 Hz)
Reference Example 18
4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.multidot.trifluoroaceta
te
30 ml of chloroform was added to 2.07 g of
N-t-butoxy-carbonyl-4-[(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline,
trifluoroacetic acid was added thereto three times in a total
amount of 8 ml, and the mixture was stirred at room temperature.
Thereafter, the solvent was removed by distillation under reduced
pressure, and the obtained residue was applied to silica gel column
chromatography to obtain 1.14 g of the title compound as reddish
white powder.
Mass (CI); m/z=325 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.88 to 1.96 (2H, m), 2.01 to 2.16 (2H,
m), 3.03 (2H, s), 3.13 to 3.36 (4H, m), 4.19 (2H, s), 5.01 (2H,
br), 6.63 (2H, d, J=8.8 Hz), 7.38 to 7.55 (5H, m), 7.73 (2H, d,
J=8.8 Hz), 12.07 (1H, br)
Reference Example 19
(a)
N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline
and (b)
N-t-butoxycarbonyl-4-[(1-benzyl-1,2,5,6-tetrahydropyridin-4-yl)acetyl]
aniline
100 ml of chloroform was added to 14.9 g of
N-t-butoxycarbonyl-4-[2-(1-benzyl-4-hydroxypiperidin-4-yl)acetyl]aniline.
After 3.1 ml of thionyl chloride was added to the mixture under ice
cooling, 11.8 ml of triethylamine was added dropwise thereto. After
the mixture was stirred at room temperature for 1 hour, water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The extract was dried over anhydrous sodium sulfate,
and the solvent was removed by distillation under reduced pressure.
The obtained residue was applied to silica gel column
chromatography to obtain the title compounds, respectively.
Compound of (a)
White powder
Mass (CI); m/z=407 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.57 (9H, s), 2.38 to 2.49 (2H, m), 2.49
to 2.67 (4H, m), 2.86 to 3.00 (2H, m), 3.56 (2H, s), 6.61 (1H, s),
6.66 (1H, s), 7.23 to 7.39 (5H, m), 7.44 (2H, d, J=8.5 Hz), 7.90
(2H, d, J=8.5 Hz)
Compound of (b)
White powder
Mass (CI); m/z=407 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.52 (9H, s), 2.11 to 2.22 (2H, m), 2.22
to 2.54 (2H, m), 2.95 to 3.04 (2H, m), 3.57 (4H, s), 5.50 to 5.56
(1H, m), 6.76 (1H, s, br), 7.19 to 7.39 (5H, m), 7.43 (2H, d, J=8.8
Hz), 7.92 (2H, d, J=8.8 Hz)
Reference Example 20
4-[(1-benzyl-4-piperidinylidene)acetyl]aniline
4.12 g of
N-t-butoxycarbonyl-4-[(1-benzyl-4-piperidinyliden)acetyl]aniline
was added to 50 ml of chloroform, and then 10 ml of trifluoroacetic
acid was added thereto. The mixture was stirred at room temperature
for 4 hours. After the reaction, the reaction mixture was condensed
under reduced pressure, and the residue was dissolved in
chloroform. Then, the solution was neutralized by adding a 28%
sodium methylate.multidot.methanol solution thereto. The residue
obtained by condensation under reduced pressure was applied to
silica gel column chromatography to obtain 2.33 g of the title
compound as bluish green powder.
Mass; m/z=306 (M.sup.+)
NMR (.delta., CDCl.sub.3); 2.29 to 2.69 (2H, m), 2.69 to 3.05 (2H,
m), 3.31 to 3.86 (4H, m), 4.22 (2H, s), 6.64 (2H, d, J=8.6 Hz),
6.71 (1H, s), 7.73 (2H, d, J=9.2 Hz)
Reference Example 21
N-t-butoxycarbonyl-4-[(1-acetyl-4-hydroxypiperidin-4-yl)acetyl]aniline
In the same manner as in Reference example 17 except for using
1-acetyl-4-piperidone in place of 1-benzyl-4-piperidone, the
reaction was carried out to obtain the title compound as white
solid.
Mass (SIMS); 377 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.37 to 1.62 (2H, m), 1.53 (9H, s ),
1.75 to 1.95 (2H, m), 2.10 (3H, s), 3.06 (2H, s), 3.47 to 3.67 (2H,
m), 4.32 to 4.47 (2H, m), 7.07 (1H, s, br), 7.50 (2H, d, J=8.8 Hz
), 7.88 (2H, d, J=8.8 Hz )
Reference Example 22
N-t-butoxycarbonyl-4-[(1-acetyl-4-piperidinyliden)acetyl]aniline
and N-t-butoxycarbonyl-4-[(1-acetyl-1,2,5,6-tetrahydropyridin-4-yl)
acetyl]aniline
In the same manner as in Reference example 14, the reaction was
carried out by using the compound obtained in Reference example 21
to obtain the mixture of the title compounds.
Yellowish white powder
Mass (CI); m/z=359 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.53 (9H, s), 2.12 and 2.16 (total 3H,
each s), 1.98 to 2.30, 2.38 to 2.57, 2.85 to 3.01, 3.38 to 3.82 and
3.82 to 4.13 (total 8H, each m), 5.45 to 5.64 and 7.01 (total 1H, m
and s, respectively), 6.75 and 7.01 (total 1H, s, respectively),
7.47 (2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz)
Reference Example 23
N-t-butoxycarbonyl-4-[(1-acetylpiperidin-4-yl)acetyl]aniline
In the same manner as in Reference example 15, the reaction was
carried out by using the mixture obtained in Reference example 22
to obtain the title compound as white powder.
Mass (CI); m/z=261 (M.sup.+ -99)
NMR (.delta., CDCl.sub.3); 1.11 to 1.32 (2H, m), 1.53 (9H, s), 1.72
to 1.90 (2H, m), 2.08 (3H, s), 2.15 to 2.34 (1H, m), 2.53 to 2.66
(1H, m), 2.82 to 2.90 (2H, m), 3.02 to 3.17 (1H, m), 3.73 to 3.85
(1H, m), 4.57 to 4.68 (1H, m), 6.79 (1H, s, br), 7.46 (2H, d, J=8.8
Hz), 7.90 (2H, d, J=8.8 Hz)
Reference Example 24
4-[(1-acetylpiperidin-4-yl) acetyl]aniline
50 ml of chloroform was added to 6.90 g of
N-t-butoxy-carbonyl-[4-(1-acetylpiperidin-4-yl)acetyl]aniline, and
trifluoroacetic acid was added to the mixture at room temperature
until no foaming occurred. The solvent was removed by distillation
under reduced pressure, water was added to the residue, and the
mixture was neutralized with sodium hydrogen carbonate and then
extracted with chloroform. After the extract was dried over
anhydrous sodium sulfate, the solvent was removed by distillation
under reduced pressure. The obtained residue was applied to silica
gel column chromatography to obtain 3.56 g of the title compound as
yellow solid.
Mass (CI); m/z=261 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.10 to 1.30 (2H, m), 1.68 to 1.91 (2H,
m), 2.08 (3H, s), 2.12 to 2.34 (1H, m), 2.48 to 2.68 (1H, m), 2.68
to 2.93 (2H, m), 3.00 to 3.17 (1H, m), 3.72 to 3.85 (1H, m), 4.54
(1H, m), 6.66 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.8 Hz)
Reference Example 25
N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline
50 ml of tetrahydrofuran was added to 3.80 g of
N-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyl
lithium.multidot.pentane solution was added dropwise thereto under
an argon stream at -78.degree. C. Subsequently, a solution of 3.50
g of (1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml of
tetrahydrofuran was added to the mixture, and the resulting mixture
was stirred until its temperature was returned to room temperature.
Then, a saturated ammonium chloride aqueous solution was added to
the reaction mixture, the mixture was extracted with ethyl acetate,
and the extract was dried over anhydrous sodium sulfate. Then, the
solvent was removed by distillation under reduced pressure, and the
obtained residue was applied to silica gel column chromatography to
obtain 4.57 g of the title compound as white powder.
Mass (CI); m/z=453 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.15 to 1.42 (4H, m), 1.42 to 1.72 (4H,
m), 1.53 (9H, s), 1.72 to 1.86 (1H, m), 1.86 to 2.08 (2H, m), 2.84
to 2.95 (2H, m), 3.50 (2H, s), 4.23 to 4.38 (1H, m), 6.86 (1H, s,
br), 7.13 to 7.40 (5H, m), 7.45 (2H, d, J=8.8 Hz), 7.89 (2H, d,
J=8.8 Hz)
Reference Example 26
4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline.multidot.trifluoroa
cetate
50 ml of dichloromethane was added to 4.55 g of
N-t-butoxycarbonyl-4-[4-(1-benzylpiperidin-4-yl)-3-hydroxybutanoyl]aniline
, and trifluoroacetic acid was added to the mixture at room
temperature until no foaming occurred. Then, the solvent was
removed by distillation under reduced pressure, and the obtained
residue was applied to silica gel column chromatography to obtain
1.21 g of the title compound as white powder.
Mass (CI); m/z=353 (M.sup.+ +1)
NMR (.delta., CDCl.sub.3); 1.22 to 2.08 (7H, m), 2.62 to 2.84 (2H,
m), 2.94 (2H, d, J=5.9 Hz), 3.42 to 3.62 (2H, m), 4.20 (3H, m, br),
6.63 (2H, d, J=8.8 Hz), 7.36 to 7.55 (5H, m), 7.73 (2H, d, J=8.8
Hz)
Reference Examples 27 TO 42
In the same manner as in Reference example 5, the following
compounds were obtained.
__________________________________________________________________________
Refer- ence example Compound Mass No. (characteristics) (m/z) NMR
(.delta., CDCl.sub.3)
__________________________________________________________________________
27 (E)-4-{3-[1-(2- 368 1.54 to 1.67 (2H, m), 1.77 to 1.86
fluorobenzyl)- (M.sup.+) (2H, m), 2.08 to 2.18 (2H, m),
piperidin-4- 2.22 to 2.37 (1H, m), 2.92 to 3.01 yl]propenoyl}- (2H,
m), 3.62 (2H, s), 6.82 (1H, nitrobenzene d, J=15.6Hz), 7.00 to 7.17
(3H, (brown liquid) m), 7.21 to 7.30 (1H, m), 7.35 to 7.43 (1H, m),
8.03 (2H, d, J= 8.8Hz), 8.31 (2H, d, J=8.8Hz) 28 (E)-4-{3-[1-(3-
384 1.46 to 1.71 (2H, m), 1.75 to 1.89 chlorobenzyl)- (M.sup.+)
(2H, m), 2.00 to 2.19 (2H, m), piperidin-4- 2.22 to 2.39 (1H, m),
2.85 to 3.04 yl]propenoyl}- (2H, m), 3.52 (2H, s), 6.83 (1H,
nitrobenzene d, J=15Hz), 7.09 (1H, dd, J=15Hz, (brown crystal)
6Hz), 7.15 to 7.41 (4H, m), 8.04 (2H, d, J=9Hz), 8.32 (2H, d, J=
9Hz) 29 (E)-4-{3-[1-(3- 381 1.53 to 1.67 (2H, m), 1.75 to 1.85
methoxybenzyl)- (CI) (2H, m), 2.01 to 2.13 (2H, m), piperidin-4-
(M.sup.+ +1) 2.24 to 2.37 (1H, m), 2.93 to 3.01 yl]propenoyl}- (2H,
m), 3.51 (2H, s), 3.82 (3H, nitrobenzene s), 6.82 (1H, d,
J=15.6Hz), 6.80 (yellowish to 6.84 (1H, m), 6.86 to 6.95 (1H, brown
crystal) m), 7.08 (1H, dd, J=15.6Hz, 8.7Hz), 7.22 to 7.28 (1H, m),
8.03 (2H, d, J=8.8Hz), 8.31 (2H, d, J=8.8Hz) 30 (E)-4-{3-[1-(2- 380
1.52 to 1.70 (2H, m), 1.70 to 1.85 methoxybenzyl)- (M.sup.+) (2H,
m), 2.05 to 2.20 (2H, m), piperidin-4- 2.20 to 2.38 (1H, m), 2.94
to 3.06 yl]propenoyl}- (2H, m), 3.59 (2H, s), 3.82 (3H,
nitrobenzene s), 6.81 (1H, d, J=15.3Hz), 6.84 (pale yellow to 6.99
(2H, m), 7.08 (1H, dd, J= crystal) 15.3 Hz, 6.7Hz), 7.19 to 7.29
(1H, m), 7.35 (1H, d, J=7.3Hz), 8.03 (2H, d, J=8.5Hz), 8.31 (2H, d,
J=8.5Hz) 31 (E)-4-{3-[1-(3- 364 1.47 to 1.71 (2H, m), 1.71 to 1.89
methylbenzyl)- (M.sup.+) (2H, m), 1.96 to 2.13 (2H, m),
piperidin-4- 2.21 to 2.40 (1H, m), 2.35 (3H, yl]propenoyl}- s),
2.88 to 3.03 (2H, m), 3.49 nitrobenzene (2H, s), 6.82 (1H, d,
J=16.9Hz), (yellow crystal) 7.02 to 7.29 (5H, m), 8.03 (2H, d,
J=8.8Hz), 8.31 (2H, d, J=8.8Hz) 32 (E)-4-{3-[1-(3- 418 1.49 to 1.70
(2H, m), 1.70 to 1.87 trifluoromethyl- (M.sup.+) (2H, m), 2.00 to
2.16 (2H, m), benzyl)piperi- 2.22 to 2.40 (1H, m), 2.85 to 2.97
din-4-yl]pro- (2H, m), 3.57 (2H, s), 6.83 (1H, penoyl}nitro- d,
J=15.9Hz), 7.09 (1H, dd, J= benzene (brown 15.9Hz, 6.7Hz), 7.37 to
7.48 (1H, liquid) m), 7.48 to 7.58 (2H, m), 7.60 (1H, s), 8.04 (2H,
d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz) 33 (E)-4-{3-[1-(4- 375 1.48 to
1.70 (2H, m), 1.75 to 1.87 cyanobenzyl)- (M.sup.+) (2H, m), 2.03 to
2.17 (2H, m), piperidin-4- 2.23 to 2.40 (1H, m), 2.82 to 2.97
yl]propenoyl}- (2H, m), 3.56 (2H, s), 6.83 (1H, nitrobenzene d,
J=15.4Hz), 7.08 (1H, dd, (yellow crystal) J=15.4Hz, 6.6Hz), 7.46
(2H, d, J=8.1Hz), 7.61 (2H, d, J=8.1Hz), 8.04 (2H, d, J=8.8Hz),
8.32 (2H, d, 8.8hz) 34 (E)-4-{3-[1-(3- 375 1.47 to 1.70 (2H, m),
1.75 to 1.89 cyanobenzyl)- (M.sup.+) (2H, m), 2.02 to 2.18 (2H, m),
piperidin-4- 2.22 to 2.44 (1H, m), 2.82 to yl]propenoyl}- 2.96 (2H,
m), 3.59 (2H, s), 6.84 nitrobenzene (1H, d, J=15.4Hz), 7.09 (1H,
dd, (brown liquid) J=15.4Hz, 6.6Hz), 7.37 to 7.50 (1H, m), 7.50 to
7.62 (2H, m), 7.66 (1H, s), 8.05 (2H, d, J=8.8Hz), 8.32 (2H, d,
J=8.8Hz) 35 (E)-4-{3-[1-(1- 400 1.46 to 1.66 (2H, m), 1.71 to 1.85
naphthylmethyl)- (M.sup.+) (2H, m), 2.04 to 2.22 (2H, m),
piperidin-4- 2.22 to 2.40 (1H, m), 2.93 to 3.07 yl]propenoyl}- (2H,
m), 3.91 (2H, s), 6.80 (1H, nitrobenzene d, J=16.3Hz), 7.07 (1H,
dd, J= (brown liquid) 16.3Hz, 6.6Hz), 7.37 to 7.55 (4H, m), 7.74 to
7.89 (2H, m), 8.02 (2H, d, J=8.8Hz), 8.30 (3H, d, 8.8Hz) 36
(E)-4-{3-[1-(.beta.- 364 1.39 (3H, d, J=6.6Hz), 1.43 to
phenethyl)piper- (M.sup.+) 2.13 (6H, m), 2.13 to 2.32 (1H,
idin-4-yl]pro- m), 2.81 to 2.93 (1H, m), 3.04 to penoyl}nitro- 3.17
(1H, m), 3.46 (1H, q, J= benzene (reddish 6.6Hz), 6.79 (1H, d,
J=15.4Hz), brown liquid) 7.06 (1H, dd, J=15.4Hz, 6.6Hz), 7.17 to
7.39 (5H, m), 8.02 (2H, d, J=8.8Hz), 8.30 (2H, d, J=8.8Hz) 37
(E)-4-{3-[1-(3- 352 1.49 to 1.68 (2H, m), 1.74 to 1.88
pyridylmethyl)- (CI) (2H, m), 2.01 to 2.16 (2H, m), piperidiin-4-
(M.sup.+ +1) 2.22 to 2.39 (1H, m), 2.83 to 2.99 yl]propenoyl}- (2H,
m), 3.54 (2H, s), 6.83 (1H, nitrobenzene d, J=15.9Hz), 7.08 (1H,
dd, J=15.9 (reddish brown Hz, 6.7Hz), 7.21 to 7.30 (1H, m),
crystal) 7.63 to 7.72 (1H, m), 8.04 (2H, d, J=9.2Hz), 8.31 (2H, d,
J=9.2Hz), 8.46 to 8.58 (2H, m) 38 (E)-4-{3-[1-(6- 366 1.53 to 1.72
(2H,m), 1.74 to 1.86 methyl-2-pyridyl- (CI) (2H, m), 2.09 to 2.24
(2H, m), methyl)piperidin- (M.sup.+ +1) 2.24 to 2.39 (1H, m), 2.55
(3H, 4-yl]propenoyl}- s), 2.93 to 3.03 (2H, m), 3.65 nitrobenzene
(2H, s), 6.83 (1H, d, J=15.3Hz), (yellowish 7.03 (1H, d, J=7.9Hz),
7.09 (1H, brown crystal) dd, J=15.3Hz, 6.7Hz), 7.55 (1H, t,
J=7.9Hz), 8.04 (2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz) 39
(E)-4-{3-[1-(2- 357 1.54 to 1.66 (2H, m), 1.76 to 1.85
thienylmethyl)- (CI) (2H, m), 2.03 to 2.15 (2H, m), piperidin-4-
(M.sup.+ +1) 2.23 to 2.36 (1H, m), 2.96 to 3.04 yl]propenoyl}- (2H,
m), 3.75 (2H, s), 6.82 (1H, nitrobenzene d, J=15.6Hz), 6.99 to 7.03
(1H, (yellow crystal) m), 7.03 to 7.06 (1H, m), 7.08 (1H, dd,
J=15.6Hz, 6.4Hz), 7.24 (1H, d, J=6.4Hz), 8.02 (2H, d, J=8.8Hz),
8.31 (2H, d, J=8.8Hz) 40 (E)-4-{3-[1-(3,4- 394 1.48 to 1.67 (2H,
m), 1.74 to 1.87 methylenedioxy- (M.sup.+) (2H, m), 1.96 to 2.11
(2H, m), benzyl)piperi- 2.20 to 2.37 (1H, m), 2.88 to 3.00
din-4-yl]pro- (2H, m), 3.43 (2H, s), 5.94 (2H, penoyl}nitro- s),
6.74 (2H, s), 6.82 (1H, d, benzene (pale J=15.9Hz), 6.85 (1H, s),
7.08 (1H, yellow crystal) dd, J=15.9Hz, 6.7Hz), 8.03 (2H, d,
J=9.2Hz), 8.31 (2H, d, J=9.2Hz) 41 (E)-4-{3-[1-(3,4- 409 1.49 to
1.72 (2H, m), 1.72 to 1.84 ethylenedioxy- (CI) (2H, m), 1.95 to
2.11 (2H, m), benzyl)piperi- (M.sup.+ +1) 2.20 to 2.36 (1H, m),
2.89 to 2.99 din-4-yl]pro- (2H, m), 3.41 (2H, s), 4.25 (4H,
penoyl}nitro- s), 6.81 (1H, d, J=15.3Hz), 6.79 benzene (brown to
6.84 (3H, m), 7.08 (1H, dd, liquid) J=15.3Hz, 6.7Hz), 8.03 (2H, d,
J=9.2Hz), 8.31 (2H, d, J=8.8Hz) 42 (E)-4-{3-[1-(2,3- 410 1.46 to
1.66 (2H, m), 1.73 to 1.85 dimethoxybenz- (M.sup.+) (2H, m), 2.02
to 2.18 (2H, m), yl)piperidin-4- 2.18 to 2.37 (1H, m), 2.94 to 3.03
yl]propenoyl}- (2H, m), 3.57 (2H, s), 3.83 (3H, nitrobenzene s),
3.87 (3H, s), 6.80 (1H, d, (brown liquid) J=15.9Hz), 6.80 to 6.86
(1H, m), 6.95 to 7.00 (2H, m), 7.07 (1H, dd, J=15.3Hz, 6.7Hz), 8.03
(2H, d, J=9.2Hz), 8.31 (2H, d, J=9.2Hz)
__________________________________________________________________________
Reference Examples 43 to 56
In the same manner as in Reference example 10, the following
compounds were obtained.
__________________________________________________________________________
Refer- ence example Compound Mass No. (characteristics) (m/z) NMR
(.delta., CDCl.sub.3)
__________________________________________________________________________
43 4-{3-[1-(2- 340 1.19 to 1.40 (3H, m), 1.54 to 1.78
fluorobenzyl)- (M.sup.+) (4H, m), 1.91 to 2.09 (2H, m),
piperidin-4- 2.77 to 2.96 (4H, m), 3.57 (2H, yl]propanoyl]- s),
4.09 (2H, s, br), 6.63 (2H, d, aniline (pale J=8.8Hz), 6.95 to 7.13
(2H, m), yellow crystal) 7.16 to 7.29 (1H, m), 7.34 to 7.43 (1H,
m), 7.80 (2H, d, J=8.8Hz) 44 4-{3-[1-(4- 356 1.23 to 1.42 (3H, m),
1.63 to 1.75 chlorobenzyl)- (M.sup.+) (4H, m), 1.85 to 2.04 (2H,
m), piperidin-4- 2.81 to 2.95 (4H, m), 3.39 to 3.54 yl]propanoyl}-
(2H, br), 4.09 (2H, br), 6.64 (2H, aniline (white d), 7.23 to 7.33
(4H, m), 7.80 crystal) (2H, d) 45 4-{3-[1-(2- 352 (CDCl.sub.3
DMSO-d.sub.6) 1.38 to 1.59 (1H, methoxybenzyl)- (M.sup.+) m), 1.59
to 1.90 (6H, m), 2.38 to piperidin-4- 2.62 (2H, m), 2.86 (2H, t, J=
yl]propanoyl}- 7.3Hz), 3.16 to 3.33 (2H, m), 3.85 aniline.HCl (3H,
s), 4.01 (2H, s, br), 4.69 salt (yellowish (2H, s, br), 6.64 (2H,
d, J= brown crystal) 8.6Hz), 6.90 to 7.03 (2H, m), 7.30 to 7.40
(1H, m), 7.54 to 7.63 (1H, m), 7.74 (2H, d, J=8.6Hz) 46 4-{3-[1-(3-
428 1.20 to 1.39 (3H, m), 1.59 to 1.74 benzyloxybenz- (M.sup.+)
(4H, m), 1.85 to 2.00 (2H, m), yl)piperidin-4- 2.79 to 3.01 (4H,
m), 3.46 (2H, yl]propanoyl}- s), 4.09 (2H, s, br), 5.06 (2H,
aniline (brown s), 6.64 (2H, d, J=8.6Hz), 6.82 to liquid) 6.91 (2H,
m), 7.18 (1H, s), 7.19 to 7.27 (1H, m), 7.31 to 7.48 (5H, m), 7.80
(2H, d, J=8.6Hz) 47 4-{3-[1-(3- 336 1.19 to 1.40 (3H, m), 1.53 to
1.77 methylbenzyl)- (M.sup.+) (4H, m), 1.84 to 2.01 (2H, m),
piperidin-4- 2.34 (3H, s), 2.76 to 2.96 (4H, yl]propanoyl}- m),
3.44 (2H, s), 4.11 (2H, s, aniline (yellow br), 6.63 (2H, d,
J=8.8Hz), 7.00 crystal) to 7.26 (4H, m), 7.80 (2H, d, J=8.8Hz) 48
4-{3-[1-(3-tri- 390 1.17 to 1.42 (3H, m), 1.56 to 1.80
fluorobenzyl)- (M.sup.+) (4H, m), 1.88 to 2.04 (2H, m),
piperidin-4- 2.79 to 2.94 (4H, m), 3.51 (2H, yl]propanoyl}- s),
4.12 (2H, s, br), 6.64 (2H, d, aniline (yellow J=8.6Hz), 7.37 to
7.45 (1H, m), crystal) 7.45 to 7.56 (2H, m), 7.57 (1H, s), 7.80
(1H, d, J=8.6Hz) 49 4-{3-[1-(4- 347 (CDCl.sub.3 -DMSO-d.sub.6) 1.13
to 1.40 (3H, cyanobenzyl)- (M.sup.+) m), 1.51 to 1.78 (4H, m), 1.87
to piperidin-4- 2.05 (2H, m), 2.69 to 2.92 (4H, yl]propanoyl}- m),
3.52 (2H, s), 4.98 (2H, s, aniline (pale br), 6.63 (2H, d,
J=8.8Hz), 7.46 brown crystal) (2H, d, J=8.1Hz), 7.60 (2H, d,
J=8.1Hz), 7.74 (2H, d, J=8.8Hz) 50 4-{3-[1-(2- 372 (CDCl.sub.3
-DMSO-d.sub.6) 1.28 to 1.50 (1H, naphthylmethyl)- (M.sup.+) m),
1.50 to 1.81 (6H, m), 2.10 to piperidin-4- 2.50 (2H, m), 2.83 (2H,
t, J= yl]propanoyl}- 7.3Hz), 2.93 to 3.27 (2H, m), 3.81 aniline.HCl
to 4.27 (2H, br), 5.29 (2H, s), salt (yellowish 6.61 (2H, d,
J=8.8Hz), 7.40 to brown crystal) 7.59 (4H, m), 7.69 (2H, d, J=
8.8Hz), 7.76 to 7.92 (2H, m), 8.23 to 8.34 (1H, m) 51 4-{3-[1-(2-
323 1.20 to 1.45 (3H, m), 1.50 to 1.80 pyridylmethyl)- (M.sup.+)
(4H, m), 1.95 to 2.15 (2H, m), piperidin-4- 2.80 to 3.00 (4H, m),
3.64 (2H, yl]propanoyl}- s), 4.09 (2H, s, br), 6.64 (2H, d, aniline
(yellow J=8.8Hz), 7.10 to 7.20 (1H, m), crystal) 7.38 to 7.47 (1H,
m), 7.60 to 7.69 (1H, m), 7.81 (2H, d, J=8.8Hz), 8.52 to 8.60 (1H,
m) 52 4-{3-[1-(3- 323 1.13 to 1.40 (3H, m), 1.54 to 1.78
pyridylmethyl)- (M.sup.+) (4H, m), 1.84 to 2.03 (2H, m),
piperidin-4- 2.75 to 2.93 (4H, m), 3.48 (2H, yl]propanoyl}- s),
4.19 (2H, s, br), 6.64 (2H, d, aniline (pale J=8.8Hz), 7.19 to 7.30
(1H, m), yellow crystal) 7.62 to 7.71 (1H, m), 7.80 (2H, d
J=8.8Hz), 8.45 to 8.58 (2H, m) 53 4-{3-[1-(4- 323 1.18 to 1.41 (3H,
m), 1.50 to 1.79 pyridylmethyl)- (M.sup.+) (4H, m), 1.89 to 2.07
(2H, m), piperidin-4- 2.73 to 2.93 (4H, m), 3.48 (2H,
yl]propanoyl}- s), 4.10 (2H, s, br), 6.64 (2H, d, aniline (pale
J=8.8Hz), 7.27 (2H, d, J=5.9Hz), yellow crystal) 7.81 (2H, d,
J=8.8Hz), 8.52 (2H, d, J=5.9Hz) 54 4-{3-[1-(6- 338 1.26 to 1.46
(3H, m), 1.62 to 1.76 methyl-4-pyrid- (CI) (4H, m), 1.97 to 2.13
(2H, m), ylmethyl)piper- (M.sup.+ +1) 2.54 (3H, s), 2.83 to 2.95
(4H, idin-4-yl]pro- m), 3.61 (2H, s), 4.10 (2H, s, panoyl}aniline
br), 6.64 (2H, d, J=9.2Hz), 7.00 (yellow crystal) (1H, d, J=7.3Hz),
7.21 to 7.30 (1H, m), 7.49 to 7.58 (1H, m), 7.81 (2H, d, J=9.2Hz)
55 4-{3-[1-(3,4- 380 1.24 to 1.38 (3H, m), 1.61 to 1.74
ethylenedioxy- (M.sup.+) (4H, m), 1.83 to 1.97 (2H, m),
benzyl)piperi- 2.81 to 2.93 (4H, m), 3.37 (2H, din-4-yl]pro- s),
4.10 (2H, s, br), 4.24 (4H, panoyl}aniline s), 6.64 (2H, d,
J=9.2Hz), 6.78 to (brown liquid) 6.82 (3H, m), 7.80 (2H, d, J=
9.2Hz) 56 4-{3-[1-(2,3- 382 1.20 to 1.37 (3H, m), 1.62 to 1.74
dimethoxybenz- (M.sup.+) (4H, m), 1.94 to 2.07 (2H, m),
yl)piperidin-4- 2.82 to 2.97 (4H, m), 3.54 (2H, yl]propanoyl}- s),
4.82 (3H, s), 3.86 (3H, s), aniline (brown 4.12, (2H, s, br) 6.64
(2H, d, J= liquid) 8.6Hz), 6.82 (1H, d, J=7.3Hz), 6.94 to 7.05 (2H,
m), 7.80 (2H, d, J=8.6Hz)
__________________________________________________________________________
Reference Examples 57 to 66
In the same manner as in Reference examples 13, 14, 15 and 16, the
following compounds were obtained.
__________________________________________________________________________
Refer- ence example Compound Mass No. (characteristics) (m/z) NMR
(.delta., (CDCl.sub.3)
__________________________________________________________________________
57 N-trifluoroace- 403 2.39 to 2.49 (2H, m), 2.49 to 2.66
tyl-4-[(1-benzyl- (M.sup.+ +1) (4H, m), 2.87 to 3.00 (2H, m),
4-piperidinylid- 3.54 (2H, s), 6.63 (1H, s), 7.17 ene)acetyl]ani-
to 7.41 (5H, m), 7.69 (2H, d, line (pale yel- J=8.5Hz), 7.97 (2H,
d, J=8.5Hz), low crystal) 8.38 (1H, br) 58 N-trifluoroace- 405 1.25
to 1.47 (2H, m), 1.63 to 1.79 tyl-4-[(1-benzyl- (M.sup.+ +1) (2H,
m), 1.87 to 2.08 (3H, m), piperidin-4-yl)- 2.76 to 2.94 (4H, m),
3.49 (2H, acetyl]aniline s), 7.18 to 7.37 (5H, m), 7.70 (pale
yellow (2H, d, J=9.1Hz), 7.97 (2H, d, crystal) J=9.1Hz) 59
N-acetyl-4-[(1- 397 1.56 to 1.90 (4H, m), 2.23 (3H,
benzyl-4-hydroxy- (M.sup.+ +1) s), 2.40 to 2.69 (4H, m), 3.09
piperidin-4-yl)- (2H, s), 3.52 (2H, s), 3.96 (3H, acetyl]-2-meth-
s), 4.10 (1H, s), 6.93 (1H, d, oxyaniline (pale J=8.5Hz), 7.17 to
7.40 (5H, m), yellow crystal) 7.67 to 7.80 (2H, m), 8.99 (1H, d,
J=2.4Hz) 60 N-acetyl-4-[(1- 379 2.22 (3H, s), 2.37 to 2.48 (2H,
benzyl-4-piperi- (M.sup.+ +1) m), 2.48 to 2.65 (4H, m), 2.88 to
dinylidene)ace- 2.99 (2H, m), 3.53 (2H, s), 3.94 tyl]-2-methoxy-
(3H, s), 6.65 (1H, s), 6.934 (1H, aniline (yellow d, J=8.5Hz), 7.20
to 7.39 (5H, m), crystal) 7.67 to 7.80 (2H, m), 8.97 (1H, d,
J=2.4Hz) 61 N-acetyl-4-[(1- 381 1.30 to 1.44 (2H, m), 1.60 to 1.78
benzylpiperidin)- (M.sup.+ +1) (3H, m), 1.93 to 2.06 (2H, m),
4-yl)acetyl]-2- 2.22 (3H, s), 2.79 to 2.91 (4H, methoxyaniline m),
3.49 (2H, s), 3.94 (3H, s), (yellowish 6.92 (1H, d, J=8.8Hz), 7.20
to brown liquid) 7.36 (5H, m), 7.72 (1H, dd, J= 8.8Hz, 2.0Hz), 7.76
(1H, s, br), 8.98 (1H, d, J=2.0Hz) 62 4-[(1-benzyl- 339 (CDCl.sub.3
-DMSO-d.sub.6) 1.66 to 1.72 (2H, piperidin-4- (M.sup.+ +1) m), 1.72
to 1.96 (2H, m), 2.09 to yl)acetyl]-2- 2.23 (1H, m), 2.88 to 3.07
(4H, methoxyaniline. m), 3.29 to 3.40 (2H, m), 3.99 2HCl salt (pale
(3H, s), 4.27 (2H, d, J=4.9Hz), brown crystal) 7.20 (1H, d,
J=8.8Hz), 7.39 to 7.46 (3H, m), 7.60 to 7.72 (2H, m), 7.92 (1H, dd,
J=8.8Hz, 2.0Hz), 7.98 (1H, d, J=2.0Hz), 10.82 (1H, br) 63
N-acetyl-4-[(1- 382 1.58 to 1.87 (4H, m), 2.82 (3H,
benzyl-4-hydroxy- (M.sup.+ s), 2.40 to 2.71 (4H, m), 3.05
piperidin-4-yl)- -18) (2H, s), 3.52 (2H, s), 3.80 (1H,
acetyl]-2-chloro- s), 7.20 to 7.36 (5H, m), 7.78 to aniline (pale
7.90 (2H, m), 7.98 (1H, d, brown liquid) J=1.8Hz), 8.56 (1H, d,
J=9.1Hz) 64 Mixture of N-ace- 383 2.08 to 2.22, 2.40 to 2.65, 2.88
tyl-4-[()1-benzyl- (M.sup.+ +1) to 3.04 and 3.30 to 3.64 (total
4-piperidinyl- 10H), 2.28 (3H, s), 5.33 and 6.60 idene-acetyl]-2-
(total 1H), 7.17 to 7.39 (5H, m), chloroaniline and 7.73 to 7.91
(2H, m), 7.96 to 8.03 N-acetyl-4-[(1- (1H, m), 8.49 to 8.57 (1H, m)
benzyl-1,2,5,6- tetrahydropyridin- 4-yl)acetyl]-2- chloroaniline
(pale brown liquid) 65 N-acetyl-4-[(1- 385 1.81 to 2.03 (2H, m),
2.03 to 2.35 benzylpiperi- (M.sup.+ +1) (3H, m), 2.28 (3H, s), 2.59
to din-4-yl)ace- 2.80 (2H, m), 2.88 to 2.99 (2H, tyl]-2-chloro- m),
3.34 to 3.53 (2H, m), 4.14 aniline.HCl (2H, s), 7.40 to 7.50 (3H,
m), salt (pale yel- 7.57 to 7.68 (2H, m), 7.77 to 7.88 low crystal)
(2H, m), 7.95 (1H, d, J=1.8Hz), 8.55 (1H, d, J=9.1Hz) 66
4-[(1-benzyl- 343 (CDCl.sub.3 -DMSO-d.sub.6) 1.82 to 2.00 (2H,
piperidin-4- (M.sup.+ +1) m), 2.00 to 2.32 (3H, m), 2.61 to
yl)acetyl]-2- 2.90 (2H, m), 2.84 (2H, d, J= chloroaniline. 6.1Hz),
3.33 to 3.53 (2H, m), 4.15 2HCl salt (pale (2H, d, J=4.9Hz), 6.89
(1H, d, brown solid) J=8.6Hz), 7.35 to 7.52 (3H, m), 7.52 to 7.74
(3H, m), 7.83 (1H, d, J=2.4Hz), 12.22 (1H, br) 67 N-acetyl-4-[(1-
397 1.61 to 1.78 (4H, m), 2.24 (3H, benzyl-4-hydroxy- (M.sup.+ +1)
s), 2.39 to 2.91 (4H, m), 3.08 piperidin-4- (2H, s), 3.53 (2H, s),
3.81 (1H, yl)acetyl]-3- s, br), 3.88 (3H, s), 6.60 (1H,
methoxyaniline dd, J=9.2Hz, 2.4Hz), 7.16 to 7.40 (pale yellow (5H,
m), 7.80 (1H, d, J=9.2Hz), liquid) 8.43 (1H, d, J=2.4Hz), 11.95
(1H, s, br) 68 N-acetyl-4-[(1- 381 1.27 to 1.46 (2H, m), 1.64 to
1.78 benzylpiperidin- (M.sup.+ +1) (2H, m), 1.83 to 2.09 (3H, m),
4-yl)acetyl]-3- 2.23 (3H, s), 2.75 to 2.94 (2H, methoxyaniline m),
2.84 (2H, d, J=6.7Hz), 3.49 (pale yellow (2H, s), 3.87 (3H, s),
6.60 (1H, liquid) dd, J=9.2Hz, 2.4Hz), 7.13 to 7.40 (5H, m), 7.81
(1H, d, J=8.6Hz), 8.42 (1H, d, J=2.4Hz), 12.15 (1H, s, br) 69
4-[(1-benzyl- 339 (CDCl.sub.3 -DMSO-d.sub.6) 1.84 to 2.33 (5H,
piperidin-4- (M.sup.+ +1) m), 2.74 to 2.98 (2H, m), 2.87
yl)acetyl]-3- (2H, d, J=6.1Hz), 3.31 to 3.50 methoxyaniline. (2H,
m), 3.82 (3H, s), 4.21 (2H, 2HCl salt d, J=4.9Hz), 6.38 (1H, dd, J=
(reddish brown 9.2Hz, 2.4Hz), 6.52 (1H, d, J= solid) 2.4Hz), 7.28
to 7.52 (3H, m), 7.52 to 7.83 (3H, m), 11.70 (1H, br)
__________________________________________________________________________
EFFECTS OF THE INVENTION
The compound having the formula (I) of the present invention has
excellent selective inhibiting activities to both of
acetylcholinesterase and A type monoamine oxidase, and is extremely
useful as an antidepressant and an agent for curing senile
dementia.
As an administration form for such purposes, there may be
mentioned, for example, oral administration by a tablet, a capsule,
a granule, a powder, syrup, etc. or parenteral administration by an
intravenous injection, an intramuscular injection, a suppository,
etc. The dose varies depending on age, body weight, symptoms, an
administration form, an administration time, etc., but it is
generally about 1 to 1,000 mg per day in one dose or divided doses
to an adult.
Test example 1. Acetylcholinesterase-inhibiting activity
As an enzyme source, a crude synaptosome fraction of a rat cerebrum
was used. The crude synaptosome fraction was prepared by
homogenizing a rat cerebrum in a 0.32M sucrose solution and, after
centrifugal operation, suspending it in a 0.1M phosphate
buffer.
The activity of acetylcholinesterase was measured by a partially
modified method of the method of Ellman et. al. (Ellman, G. L. et
al., Biochem. Pharmacol., 7, 88 (1961)). That is, to the crude
synaptosome fraction of the rat cerebrum suitably diluted with a
0.1M phosphate buffer were added each compound to be tested,
5,5'-dithiobis(2-nitrobenzoic acid) (hereinafter referred to as
DTNB) and acetylthiocholine as a substrate, and the mixture was
incubated at 25.degree. C. for a predetermined time. Subsequently,
the amount of yellow anions formed by reaction of acetylthiocholine
and DTNB was measured as absorbance at 410 nm to determine the
activity of acetylcholinesterase.
Enzyme activity-inhibiting rates were calculated from absorbances
in the presence of the compounds to be tested having various
concentrations based on absorbances in the absence of the compounds
to be tested, with absorbance when reaction was carried out in the
absence of the substrate being defined as blank. IC.sub.50 values
were calculated by Hill analysis.
Test example 2. Butyrylcholinesterase-inhibiting activity
As an enzyme source, a rat serum was used.
The activity of butyrylcholinesterase was measured by a partially
modified method of the above method of Ellman et. al. That is, to
the rat serum suitably diluted with a 0.1M phosphate buffer were
added each compound to be tested, DTNB and butyrylthiocholine as a
substrate, and the mixture was incubated at 25.degree. C. for a
predetermined time. Subsequently, the amount of yellow anions
formed by reaction of butyrylthiocholine and DTNB was measured as
absorbance at 410 nm to determine the activity of
butyrylcholinesterase.
Enzyme activity-inhibiting rates were calculated from absorbances
in the presence of the compounds to be tested having various
concentrations based on absorbances in the absence of the compounds
to be tested, with absorbance when reaction was carried out in the
absence of the substrate being defined as blank. IC.sub.50 values
were calculated by Hill analysis.
Test example 3. A type and B type monoamine oxidase-inhibiting
activity
As an enzyme source, a rat cerebrum homogenized in a 0.1M phosphate
buffer was used.
The activities of monoamine oxidases were measured by a partially
modified method of the method of Da Prada et al. (Da Prada, M. et
al., J. Pharmacol. Exp. Ther., 248 (1), 400 (1989)). That is, the
rat cerebrum homogenate suitably diluted with a 0.1M phosphate
buffer and each compound to be tested were preincubated at
37.degree. C. for 30 minutes. Then, a substrate labeled with
.sup.14 C (5-hydroxy-tryptamine (5-HT) having a final concentration
of 200 .mu.M was used in measurement of the activity of A type
monoamine oxidase, and .beta.-phenylethylamine (.beta.-PEA) having
a final concentration of 20 .mu.M was used in measurement of the
activity of B type monoamine oxidase) was added to the preincubated
mixture, and the mixture was incubated at 37.degree. C. for a
predetermined time. After the reaction was terminated by adding
hydrochloric acid (final concentration; 1.2M), the reaction mixture
and a predetermined amount of an organic solvent (diethyl ether was
used in measurement of the activity of A type monoamine oxidase,
and heptane was used in measurement of the activity of B type
monoamine oxidase) were vigorously stirred so that deaminated
metabolites were extracted into the organic layer. After the
mixture was separated into two layers by centrifugation, a part of
the organic layer was mixed with liquid scintillation cocktail.
Radioactivity extracted into the organic layer was measured by a
liquid scintillation counter to calculate the enzyme activity.
Inhibiting rates were calculated from enzyme activities in the
presence of the compounds to be tested having various
concentrations based on enzyme activities in the absence of the
compounds to be tested, with absorbance when reaction was carried
out in the absence of the homogenate being defined as blank.
IC.sub.50 values were calculated by Hill analysis.
The results of Test examples 1 to 3 are shown in Table 3.
TABLE 3
__________________________________________________________________________
IC.sub.50 value (M) Inhibition Inhibition Inhibition of Inhibition
of of A type of B type Compound to acetylcholin- butyrylcholin-
monoamine monoamine be tested esterase esterase oxidase oxidase
__________________________________________________________________________
Compound of 3.3 .times. 10.sup.-9 >10.sup.-5 1.6 .times.
10.sup.-6 >10.sup.-5 Example 1 Compound of 3.6 .times. 10.sup.-9
>10.sup.-5 8.9 .times. 10.sup.-7 >10.sup.-5 Example 2
Compound of 3.1 .times. 10.sup.-9 >10.sup.-5 2.2 .times.
10.sup.-7 >10.sup.-5 Example 6 Compound of 2.0 .times. 10.sup.-9
>10.sup.-5 8.5 .times. 10.sup.-8 >10.sup.-5 Example 8
Compound of 1.4 .times. 10.sup.-9 >10.sup.-5 1.4 .times.
10.sup.-6 >10.sup.-5 Example 9 Compound of 1.1 .times. 10.sup.-9
>10.sup.-5 3.2 .times. 10.sup.-7 >10.sup.-5 Example 10
Compound of 2.0 .times. 10.sup.-8 >10.sup.-5 6.0 .times.
10.sup.-7 >10.sup.-5 Example 21 Compound of 7.3 .times.
10.sup.-9 >10.sup.-5 8.1 .times. 10.sup.-7 >10.sup.-5 Example
22 Compound of 2.5 .times. 10.sup.-7 >10.sup.-5 3.4 .times.
10.sup.-7 6.8 .times. 10.sup.-6 Example 25 Compound of 1.5 .times.
10.sup.-7 >10.sup.-5 5.6 .times. 10.sup.-8 >10.sup.-5 Example
26 Compound of 1.7 .times. 10.sup.-8 >10.sup.-5 8.5 .times.
10.sup.-8 >10.sup.-5 Example 53 Compound of 2.7 .times.
10.sup.-7 >10.sup.-5 3.5 .times. 10.sup.-8 >10.sup.-5 Example
87 Compound of 3.3 .times. 10.sup.-7 >10.sup.-5 2.5 .times.
10.sup.-7 2.1 .times. 10.sup.-6 Example 88 Compound of 2.0 .times.
10.sup.-7 >10.sup.-5 4.2 .times. 10.sup.-7 7.2 .times. 10.sup.-6
Example 93 Compound A 7.3 .times. 10.sup.-9 3.9 .times. 10.sup.-6
>10.sup.-5 >10.sup.-5 Compound B >10.sup.-5 >10.sup.-5
1.6 .times. 10.sup.-7 >10.sup.-5
__________________________________________________________________________
Compound A:
1benzyl-4-[(5,6dimethoxy-1-indanon)-2-yl]methylpiperidine Compound
B: 4(4-cyanoanilino)-5,6-dihydro-7H-cyclopenta-[d]pyrimidine
* * * * *